Ms Anita Burgun

M Jacques Demongeot

Ms Catherine Deneux

Ms Chantal Reynaud

M Pierre Legrain

Marie-José Leroy

The visit took place on December 13, 2010 at the Laboratory U 936 INSERM "Conceptual modelling of biomedical knowledge". After an introduction by the Director, A. BURGUN and a closed meeting between the Committee members, the review of the past activity during the two last years, and then the future scientific project of the unit have been presented successively by A. BURGUN and O. DAMERON. After this general presentation, three actions have been detailed:

-Mining electronic health Records for improving CT recruitment: Web Semantic approach -Computer assisted decision in tele-cardiology -Inter-specific comparison between metabolic pathways.

The visit ended with meetings planned by the AERES regulation, with researchers, post-docs, PhD students, the ITA and IATOS personnel, and eventually with the representatives of the University and of INSERM.

 History and geographical localization of the research unit, and brief presentation of its field and scientific activities

This unit has been created in 2009 and is located at the Faculty of Medicine of Rennes inside of the Health Campus of Pontchaillou. The main research topic of the unit is the conceptual modelling of the biomedical knowledge in the framework of dedicated ontologies, necessary step before building Data and Knowledge Base Management Systems, or Data and Knowledge Warehouses and Repositories.

 Management team

The management team includes: A meeting was held with some of the researchers of the group, which consists of permanent Faculty of Medicine and University Hospital members corresponding to 3 professors, 3 assistant professors, and 3 University Hospital assistants. There are no full-time research scientists or research directors. The group makes significant contributions to teaching. Two of the members are responsible of a Master2. Three of the members have their Habilitation à Diriger des Recherches (HDR). One of them will retire soon. Three assistant professors of the group should receive their HDR in the next 4 years.

Researchers suffer from a recruitment problem concerning both permanent research members and engineers. New permanent positions have not been created since 2007. It is essential to rapidly strengthen the team with new University or INSERM members to assist both teaching and research activities, to ensure the viability of the group and the success of the many projects it is involved in. Recruitment difficulties are due to the lack of positions but also to the lack of attractiveness of the team. So, the researchers would strongly support a restructuring of their group.

A joined operation with other health STIC research groups would be for th researchers an opportunity to increase the size of the team and consequently its visibility and attractiveness. Collaborations have been developed in the last two years with some of these teams located in Rennes (Unité VisAGeS and LTSI) and a restructuration implying these teams seems to constitute a logical solution to the visibility and attractiveness issues.

The meeting with ITA and IATOS personnel has shown a great motivation and involvement in the life and research activities of the unit, but most engineers come from the University Hospital and not from the Faculty of Medicine. Furthermore, one engineer will leave in 2011 and the position will be lost. The rapid recruitment of a research engineer coming from INSERM of from the University is critical.

 Overall appreciation on the research unit  Summary

Despite the weak number of permanent researchers (6) and the absence of full-time researcher without teaching and/or hospital duties, the scientific productivity is very good in specialized journals of the domain (medical informatics). The unit represents the only French centre having an international visibility on the structuration of medical terminology and biomedical knowledge in the framework of ontologies, necessary before any data or knowledge organized repository (like data or knowledge bases and warehouses) building in medicine.

 Strenghts and opportunities

The monopolistic situation of the unit is very favourable to be recognized as the national reference center in biomedical ontologies, whose expertise could be used by French Faculties of Medicine, University Hospitals and research institutions like INSERM and CNRS. The presence of the unit in several FP7 European projects is a good opportunity to enlarge its international visibility.

 Weaknesses and threats

The unit needs a rapid recruitment in terms of full-time researcher (e.g., at INSERM or CNRS), as well as the consolidation (in terms of academic position) of at least one non-permanent research engineer. If not, the enthusiasm and energy of the start could disappear causing dangerous damages to the present creativity and solidarity of the unit. The papers corresponding to conferences or oral presentations in excellent international conferences (AMIA, Medinfo,…) could be often doubled by publications in the best international journals of the domain of the unit, medical informatics.

 Recommendations

The research axes of the unit are very promising and have to be deepened and reinforced so that the unit could become the reference in terms of medical knowledge organization and management in Europe. A reflexion about the possible convergence with other research units on the Rennes Health site must be pursued during the next quinquennial period.

 Production results

The scientific production is very good by taking into account the weak number of permanent researchers and the absence of full-time researchers in the unit. 21 scientific papers produced by the unit during the 5 past years (2006-2010) have been published essentially in very good journals of the disciplines "medical informatics", "bio-informatics" and "medical imaging", plus 22 papers from excellent international conferences (AMIA, Medinfo,…), plus some articles on the clinical side, which corresponds to a very good research activity for only 6 permanent researchers with teaching duties: The director of the unit has a good international visibility in its research field, i.e., medical informatics: 8 as ISI h-index and 19 as Google Scholar h-index (the best ISI h-index in this field in France is equal to 22).

 3 in BMC Bio-

 Specific comments  Appreciation on the results

The research done in this unit in the domain of biomedical knowledge management is original, generic and promising. It is already used in several projects of medical data and knowledge bases or warehouses. The quality of the publication activity is attested by not only the number but also the notoriety of the journals and congresses in which appear the papers written by the researchers of the unit. The impact in terms of patents and exploitation licensing weak, but an interesting industrial partnership is present in the European FP7 project EHR4CR with pharmaceutical industry, as well as in the project Akenaton and its extension "Off-site Cardiology" with the European company SORIN and could occur from the project Astec with the regional Cancero-Pole Onco-Bretagne and from the project "Interspecies comparison of metabolic pathways" with the national institution INRA devoted to agronomic research. Ancient collaborations exist about the tools for combining voice recognition and automatic indexing of medical reports with the company Intermède and a new partnership is starting with the company IBC (Integrative BioComputing) for the development of serious games in the framework of the French Virtual Medical University.

 Appreciation on the impact, the attractiveness of the research unit and of the quality of its links with international, national and local partners

The unit has an international visibility allowing welcoming PhD students and post-doctoral fellows in the framework of FP7 European projects. The ancient and deep link with the National Library of Medicine ensures also a good flux of international collaborations and invitations in excellent international congresses in medical informatics like AMIA and Medinfo.

 Appreciation on the management and life of the research unit

The unit is well managed and the stabilization of a secretary devoted to helping the director in administrative tasks has been a good decision. Three promising cutting edge projects have emerged during the two past years, "Mining electronic health Records for improving CT recruitment: Web Semantic approaches", "Off-site Cardiology" and "Interspecies comparison of metabolic pathways". The staff members are involved in teaching in 2 research masters (MTIB-H & Bioinfo) and participating to the scientific life of the local of the Doctoral School VAS (Vie-Agro-Santé).

 Appreciation on the scientific strategy and the project

The close link between the hospital information system and the health research area favored by the involvement of INSERM is a strong point of the group. The research deals with very important, difficult and challenging problems in knowledge methodology that arise in many applications including biomedical ones when we have to integrate heterogeneous data. These problems have a great interest both from a scientific point of view and in terms of real-life biomedical applications. The solutions involve construction of models or ontologies and their use for semantic interoperability. The team presents significant contributions in this field.

The scientific contributions of the unit U 936 are guided by a constant strategy taking into account application requirements, searching systematically to detect if they are not specific of a given application in order to reach a global and high level genericity allowing their reuse (with a minor reengineering) in other projects related to various biomedical themes. The team has acquired for many years a solid expertise in the UMLS. Also it is of a small size, its dynamism is well established. Active and well-chosen collaborations at international level have been developed with NIH/NLM, Stanford and Edinburgh Universities.

The unit is involved in several funded research projects at national level (through ANR, ACI or regional funding) and at EU level (through 2 FP7 projects recently obtained). The number of different projects is impressive. Ontologies and software systems have been produced and made available on the Web.

The team has a clear scientific strategy. Its project is in the continuity of the research work being currently carried out. The aim is to consolidate and to develop it. One direction is to explore the applicability of its results in the context of data warehouse operational applications and to ensure a faster exchange of information flows between research and care units.

The project is articulated around two main issues: integration of biomedical data and improvement of reasoning mechanisms on these data. Both issues will often be studied in the same research project related to a given medical topic. On the integration issue, the problems of establishing relationships between data elements and ontologies, multi-domain and multi-scale knowledge integration and similarity measures will be investigated. All these problems are interesting and very relevant. The team possesses the necessary knowledge to achieve excellent results. On the reasoning issue, the major focuses will be on information at different levels of granularity, cooperation of rules and DL in an optimal way, exploiting non formal relationships and medical context. All these problems will be studied in the setting of biomedical applications but they arise in many other fields. They are important and challenging issues. The team has the skills to contribute to innovative solutions on these aspects too.

Integration and reasoning problems will be investigated through three main applications: off-site cardiology, mining electronic health records for improving recruitment in clinical tests, and interspecies comparison of metabolic pathways. These health problems are very important because they provide real requirements and allow evaluation of solutions by real users. Dealing with real problems is very often complex. The team manages very well that point thanks to the association of researchers in computer science, knowledge management, ontology engineering, semantic web, who are also experts in the health domain.

To conclude, the relevance and feasibility of a long term (5 years) scientific project is clearly proved, the resources (in particular those coming from external sources as ANR and EU) are ensured and the 3 specific projects presented are sufficiently original and necessary to guarantee a place quite apart for the unit in the French community of medical informatics.

 Appreciation project by project

1) Mining electronic health Records for improving CT recruitment : Web Semantic approaches

The project concerns the use of ontology to represent both patient data and eligibility criteria for entering in cohorts for multi-site health inquiries. The project implies the development and integration of different tools:

-a unique terminology identifier for concepts -tools of subsumption reasoning in a proper ontology -SWRL (Semantic Web Rule Language) to be combined with OWL -a reasoning tool over data types and time intervals -use of NCI Thesaurus (National Cancer Institute USA) -good coverage of domain specific terminologies -development in Open Source (no licence fees like for SNOMED)

The first developments have been already converted in OWL (Ontology Web Language) Land the research activity is pursued in the same direction. For example, the knowledge embedded in the ontology allowing for example to recognise the prostate adeno-carcinoma as a malignant neoplasm. This project is promising and should improve the relationship already existing between the unit and the clinicians of the University Hospital if it develops new end-user interface tools. The knowledge representation requires indeed effort: needing to stay within the boundaries of SWRL expressivity and idioms, implying the use of: i) no explicit disjunction, needing to use separate rules, ii) a match of an instance in a relation, and then iii) type checking methods. The criteria are written in a higher level representation, and then automatically compiled into SWRL.

The project is important and follows the successful project Astec of reuse of patient data in pharmacogenetic and pharmaco-physiologic cohorts.

2) Off-site Cardiology

This project is the following of the project AKENATON (Automated Knowledge Extraction from medical records iN Association with a Telecardiology Observation Network). After a proof of concept, the project aims in collaboration with the company SORIN (implanted cardiac devices) to achieve:

-development of an ontology in cardiology including medical reasoning rules represented in SWRL -extraction of clinical information from patient data files and exit letters -contextualisation of alarms from clinical data coming from portable devices (like permanent pacemakers) -integration of clinical data within existing standards and creation of norms from the French register of cardiac pathologies of rhythm (SFC) -at home surveillance of pacemaker implanted patients -materio-vigilance long-term testing This project would lead to a European standard co-developed with the major European company of the domain (SORIN) for following and watching at home cardiac patients with risks in major troubles of the cardiac rhythm (tachy-and bradycardiopathies, fibrillation,…).

3) Interspecies comparison of metabolic pathways

This new project concerns a comparative study of the control of the lipid metabolism in collaboration with INRA. It involves a work on animal models to extract a common explanatory knowledge about the lipid regulation, and then start an application on human implying therapeutic proposals.

The main objectives of the project are:

-To develop generic methods for comparing metabolic pathways between species on both qualitative and quantitative sides, using the Wang semantic distance (after Wang et al. in Bioinformatics 2007) -Validate these methods exploiting new experimental data (chicken), existing annotated data (human and mice) and knowledge bases (like BioCyc for biochemical reactions, GDB or UniProt, in which a gene or an enzyme "annotated to a term can be retrieved not only with this term, but also with all of its parent terms, increasing flexibility and power when searching for and making inferences about genes" as noticed by Rhee et al. in Nature Genetics 2008), ontologies (like GO, GeneOntology, for organizing genomic concepts) and specialized literature. This project will offer a new tool of information query on the web, called Go2Pub, already more performing than Pubmed in some contexts. The approach proposed is original and could be capitalized in the lipid context and, then, repeated and exploited in other metabolic contexts.

Report 1 

 1 Introduction Date and execution of the visit

  -a director : A. BURGUN, -a deputy director : O. DAMERON -a secretary manager : D. GUILLOTIN  Staff members (on the basis of the application file submitted to the engineers, technicians and administrative staff without a tenured position (Form 2.6 of the application file) 3.5 N6: Number of Ph.D. students (Form 2.7 of the application file) 6 N7: Number of staff members with a HDR or a similar grade 3 2

A1:

  Number of permanent researchers with teaching duties (recorded in N1) who are active in research 6 A2: Number of permanent researchers without teaching duties (recorded in N2) who are active in research 0 A3: Ratio of members who are active in research among staff members [(A1 + A2)/(N1 + N2)] 1 A4: Number of HDR granted during the past 4 years 0 A5: Number of PhD granted during the past 4 years 8

  informatics (ISI IF 3.43 ; ISI mathematical and computational biology journal ranking 4/29)

	 4 in Int. J. in Medical Informatics (ISI IF 3.13 ; ISI medical informatics journal ranking 3/23)
	 2 in J. of Biomedical Informatics (ISI IF 2.43 ; ISI medical informatics journal ranking 6/23)
	 3 in Artificial Intelligence in Medicine (ISI IF 1.65 ; ISI medical informatics journal ranking 13/23)
	 1 in Medical Informatics Internet Med. (ISI IF 1.04 ; ISI medical informatics journal ranking 17/23)
	 1 in J. Nuclear Medicine (ISI IF 6.42 ; ISI radiology, nuclear medicine and medical imaging journal ranking
	1/104)
	 1 in Eur. J. Nuclear Med. (ISI IF 4.5 ; ISI radiology, nuclear medicine and medical imaging journal ranking
	7/104)
	 1 in Am. J. of Neuroradiology (ISI IF 3.3 ; ISI radiology, nuclear medicine and medical imaging journal ranking
	16/104)
	 1 in Radiation Oncology (ISI IF 2.53 ; ISI radiology, nuclear medicine and medical imaging journal ranking
	32/104)
	 4 in J. of Radiology (ISI IF 0.63 ; ISI radiology, nuclear medicine and medical imaging journal ranking 94/104)

 14 in Studies in Health Technologies and Information  5 in AMIA Annual Sympsium Proceedings  2 in Lecture Notes in Computer Science  1 in Lecture Notes in Bioinformatics

Statistiques de notes globales par domaines scientifiques

  (État au 06/05/2011)

	Intitulé UR / équipe	C1	C2	C3	C4	Note globale
	MODÉLISATION CONCEPTUELLE DES CONNAISSANCES BIOMÉDICALES	A+	A+	A+	A+	A+
	C1 Qualité scientifique et production
	C2 Rayonnement et attractivité, intégration dans l'environnement
	C3 Gouvernance et vie du laboratoire
	C4 Stratégie et projet scientifique

Sciences du Vivant et Environnement

	Note globale	SVE1_LS1_LS2	SVE1_LS3	SVE1_LS4	SVE1_LS5	SVE1_LS6	SVE1_LS7	SVE2 _LS3 *	SVE2_LS8 *	SVE2_LS9 *	Total
	A+	7	3	1	4	7	6		2		30
	A	27	1	13	20	21	26	2	12	23	145
	B	6	1	6	2	8	23	3	3	6	58
	C	1					4				5
	Non noté	1									1
	Total	42	5	20	26	36	59	5	17	29	239
	A+	16,7%	60,0%	5,0%	15,4%	19,4%	10,2%		11,8%		12,6%
	A	64,3%	20,0%	65,0%	76,9%	58,3%	44,1%	40,0%	70,6%	79,3%	60,7%
	B	14,3%	20,0%	30,0%	7,7%	22,2%	39,0%	60,0%	17,6%	20,7%	24,3%
	C	2,4%					6,8%				2,1%
	Non noté	2,4%									0,4%
	Total	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%
	*

les résultats SVE2 ne sont pas définitifs au 06/05/2011. Intitulés des domaines scientifiques Sciences du Vivant et Environnement • SVE1 Biologie, santé SVE1_LS1 Biologie moléculaire, Biologie structurale, Biochimie SVE1_LS2 Génétique, Génomique, Bioinformatique, Biologie des systèmes SVE1_LS3 Biologie cellulaire, Biologie du développement animal SVE1_LS4 Physiologie, Physiopathologie, Endocrinologie SVE1_LS5 Neurosciences SVE1_LS6 Immunologie, Infectiologie SVE1_LS7 Recherche clinique, Santé publique • SVE2 Ecologie, environnement SVE2_LS8 Evolution, Ecologie, Biologie de l'environnement SVE2_LS9 Sciences et technologies du vivant, Biotechnologie SVE2_LS3 Biologie cellulaire, Biologie du développement végétal


M Philippe Moullier

M Ali

M Jacques

M François

M Moncef Guenounou

M François Lemoine

M Yves Gaudin

M Jacques Girardeau

The visit was performed the 13th of December 2010 from 13h15 to 18h30. After the introduction talk from the head of the laboratory, the main PIs were invited to present their work and project. This was followed by a general discussion focusing on science first, then on governance and general strategy. The committee then met successively in the absence of the director, students and post-docs, technicians and engineers, researchers and teachers/researchers. The visit ended by a closed-door debriefing of the committee.

 History and geographical localization of the research unit, and brief presentation of its field and scientific activities :

Since 1996, the research used recombinant viral vectors including rAAV vectors to develop gene therapy strategies for inherited diseases. During the last years, UMR INSERM 649 focused on rAAV related technology and development of pre clinical models in order to validate geen therapy strategies. A preclinical vector core as well as a large animal core has been built and developed with an IBISA labelling. Using these platforms, validations of different gene therapy strategies have been validated using preclinical large animal models leading to the implementation of clinical trials.

In addition, the research unit has proposed to study the mode of delivery of rAAV vectors, the molecular characterization of recombinant DNA, epigenetic status of the vectors within the tissue and the relationship between the host immune system and the vectors.

 Management team :

The head of the unit, Philippe MOULLIER, is a DR2 INSERM. The research unit is organized and run as one single research team with two PIs (both DR2 INSERM). Both PIs participate to the management of the unit.

 Staff members (on the basis of the application file submitted to the AERES): 2  Overall appreciation on the research unit  Summary :

In the last years, beside the research activities, different platforms for preclinical vector core, large animal core and GMP grade vector core has been built and labelled as IBISA platforms. Using these tools, the research is mainly focused on the use of rAAV vectors to develop gene therapy strategies for neuromuscular and retinal inherited diseases. Objectives are to validate strategies using large animal preclinical models (cats, dogs, monkeys); to evaluate the immunological aspect of the use of rAAV vectors (immunotoxicity, immune response and control of immune by inducing tolerance against vector and transgenes), to test different modes of delivery of rAAV vectors and to study epigenetic status of vectors once delivered within the tissue.

 Strengths and opportunities:

-Strong and visible expertise in the field of AAV based gene therapy.

-Unique access to large animal models.

-Very good clinical pipelines from pre-GMP production to phase I trials.

-Dynamic organization of the lab including fundraising.

 Weaknesses and threats:

-Lack of support from the university.

-Too many people in non academic position with low turn over.

-Concerns about the relevance of some animal models for preclinical studies.

 Recommendations:

-The Unit has to attract foreign post-docs and students.

-The goals of the immunological program should be clarified.

-There is a need to implement clinical trials within the next assessment period.

-There is also a need a global strategy from the institutions and the lab to coordinate and build a larger gene therapy effort in Nantes.

 Production results: In the last years, the head of the unit has contributed strongly to the development of a preclinical vector core a BL2/BL3 large animal core in collaboration with the veterinary school and more recently to a GMP grade vector core in collaboration with EFS. All these platforms received an IBISA labelling and represent an important and relevant support for the development of the research. However, they are not part of the present evaluation.

The research activities are based on the development of gene therapy strategies for inherited diseases using rAAV vectors. Due to the expertise and the know how in the field of rAAV vectors and in the use of preclinical large animal models, the research is original and is focused on translation to the clinic.

The two leaders of this research unit work on the development of rAAV gene therapy for neuromuscular inherited diseases and retinal inherited with clinicians and other national partners in this field (AFM, Institut of Myology) respectively. The researchers have established strong partnership with EFS and veterinary school. They participate at european and international levels to different networks (Clinigene Network of Excellence) and have strong collaborations with the University of Florida.

The research team is publishing regularly in the top journals of the speciality such as Molecular Therapy (n= 10, IF= 6.8) and Journal of Virology (n= 3, IF = 5.5). 26 publications have been published since 2006, whose only 5 of them are from collaborations.

However the number of graduate PhDs is relatively low and the quality and a small number of publications could be published in higher impact journals.

 Appreciation on the impact, the attractiveness of the research unit and of the quality of its links with international, national and local partners:

Both leaders are invited to national and international meetings at least once a year. Students also participate in national meetings and even in some cases in international meetings (ASGT and ESGT). The laboratory is capable of recruiting master and PhD students locally or at the national level. In 2010, a post-doc has been recruted for a CR1 INSERM position.

However attracting students or post-docs from abroad has not been successful. This may be reinforced in the future by a tight collaboration with the University of Florida with possibilities of international exchanges.

Leaders are able to raise funds either from local donations and private enterprises or from AFM. The strong support of AFM allows to maintain the salaries of numerous students, post-docs, technicians and engineers.

However, the support from the university appears very low, except concerning housing in the university building.

 Appreciation on the management and life of the research unit:

The research unit organisation is well structured with two small groups in a whole unit each directed by a leader. Lab meetings and invited conferences are regularly organized. Students and techincians can participate in teaching activities as well as technical formations. They can also participate in scientific presentations at meetings.

 Appreciation on the scientific strategy and the project:

The project of the reseach unit is to develop translationnal research for gene therapy of inherited diseases based on the use of rAAV vectors from bench to bedside . This project is a continuum of the previous research with the goal of enhancing translationnal gene therapy activities for retinal and neuromuscular inherited diseases.

Both projects rely on development of animal models with their avantages and their limits.

Concerning retinal inherited diseases, three projects are mainly in development, and one is almost ready to start for a clinical trials (RPE 65 gene therapy). Recent data on a phosphodiesterase 6 beta deficiency are promising for future clinical developments.

Concerning neuromuscular inherited diseases, projects for Duchenne disease as well as spinal muscular atrophy are part of collaborative networks with AFM, Genethon and Institute of Myology (Pitié Salpêtrière). The later project concerning SMA has been recently reinforced by the arrival in the research unit of a neurosurgeon whose the goal is to test different strategies for injecting rAAV vectors in the CNS. These projects are very ambitious and are long term project. With the strong support from AFM and the expertise and know how of the searchers in the field they appear feasible.

Different important questions regarding vector integration, epigenetic modifications as well as immune response and immune tolerance are addressed. However, the immune project should be clarified particularly concerning the development of strategies based on the induction of tolerance. Stronger collaborations with other immunologists in Nantes will be helpful.

Finally, to avoid exclusive private-derived fundings, a support from the academic institutions such as the university is needed.



  Date and execution of the visit :

(

  cf. http://www.aeres-evaluation.fr/IMG/pdf/Criteres_Identification_Ensgts-Chercheurs.pdf) A1: Number of permanent researchers with teaching duties (recorded in N1) who are active in research 4 A2: Number of permanent researchers without teaching duties (recorded in N2) who are active in research 5 A3: Ratio of members who are active in research among staff members [(A1 + A2)/(N1 + N2)] A4: Number of HDR granted during the past 4 years 0 A5: Number of PhD granted during the past 4 years 6 3  Specific comments  Appreciation on the results:

Sciences du Vivant et Environnement

				Statistiques de notes globales par domaines scientifiques
						(État au 06/05/2011)
		Note globale	SVE1_LS1_LS2	SVE1_LS3	SVE1_LS4	SVE1_LS5	SVE1_LS6	SVE1_LS7	SVE2 _LS3 *	SVE2_LS8 *	SVE2_LS9 *	Total
		A+	7	3	1	4	7	6		2		30
		A	27	1	13	20	21	26	2	12	23	145
		B	6	1	6	2	8	23	3	3	6	58
		C	1					4				5
		Non noté	1									1
		Total	42	5	20	26	36	59	5	17	29	239
		A+	16,7%	60,0%	5,0%	15,4%	19,4%	10,2%		11,8%		12,6%
		A	64,3%	20,0%	65,0%	76,9%	58,3%	44,1%	40,0%	70,6%	79,3%	60,7%
		B	14,3%	20,0%	30,0%	7,7%	22,2%	39,0%	60,0%	17,6%	20,7%	24,3%
		C	2,4%					6,8%				2,1%
		Non noté	2,4%									0,4%
		Intitulé UR / équipe Total 100,0%	C1 100,0%	C2 100,0%	C3 100,0%	C4 100,0%	globale Note 100,0%	100,0%	100,0%	100,0%	100,0%
	RETINAL AND NEUROMUSCULAR DISEASES TRANSLATIONAL GENE THERAPY FOR *	A	A+	A+	A	A
	C1	Qualité scientifique et production
	C2	Rayonnement et attractivité, intégration dans l'environnement
	C3	Gouvernance et vie du laboratoire
	C4	Stratégie et projet scientifique

les résultats SVE2 ne sont pas définitifs au 06/05/2011. Intitulés des domaines scientifiques Sciences du Vivant et Environnement • SVE1 Biologie, santé SVE1_LS1 Biologie moléculaire, Biologie structurale, Biochimie SVE1_LS2 Génétique, Génomique, Bioinformatique, Biologie des systèmes SVE1_LS3 Biologie cellulaire, Biologie du développement animal SVE1_LS4 Physiologie, Physiopathologie, Endocrinologie SVE1_LS5 Neurosciences SVE1_LS6 Immunologie, Infectiologie SVE1_LS7 Recherche clinique, Santé publique • SVE2 Ecologie, environnement SVE2_LS8 Evolution, Ecologie, Biologie de l'environnement SVE2_LS9 Sciences et technologies du vivant, Biotechnologie SVE2_LS3 Biologie cellulaire, Biologie du développement végétal


Ms Berthe-Marie Imbert-Marcille

M Ali

M Jacques

M François

M Moncef Guenounou

M François Lemoine

M Yves Gaudin

M Jacques Girardeau

M Olivier Garraud

The visit was performed the 13th of December 2010 from 7h45 to 12h45. After the introduction talk from the head of the laboratory, the main PIs were invited to present their work and project. This was followed by a general discussion focusing on science first, then on governance and general strategy. The committee then met successively in the absence of the director, students and post-docs, technicians and engineers, researchers and teachers/researchers. The visit ended by a closed-door debriefing of the committee.

 History and geographical localization of the research unit, and brief presentation of its field and scientific activities:

The team "Immunovirology and Genetic Polymorphism" (EA4271) was created in January 2008 and resulted from the fusion of two pre-existing research groups located in Nantes (former JE2437 and EE0503). This team is located in the Faculty of Medicine and Pharmacy (former JE2437, so called "virus group") and within the Etablissement Français du Sang (EFS, "NK group"). The EA4271 team is affiliated with the IFR26.

The unit is currently subdivided into two groups: the NK/EFS group (former EE0503) and the virus group (former JE2437). The research unit has an interest in persistent viral infections (DNA viruses and HIV), host cellular responses and genetic polymorphism (host and virus). Three research themes have been developed over the last three years.

The first theme aims at evaluating the role of dendritic cell (DC)/natural killer (NK) cell cross-talk in the context ofherpesvirus (cytomegalovirus and HHV6) infection, which occurs in immunocompromised individuals (allografts, HIV infection). This project is currently under development. The second theme (NK group) aims at analyzing KIR/HLA immunogenetics and the mechanisms of human NK cell alloreactivity after haematopoietic stem cell (HSC) graft. The third theme (virus group) aims at improving the understanding and therapeutic management of viral opportunistic complications (Herpesvirus) after allograft (HSCT or kidney transplanted patients) and at evaluating the efficacy of antiretroviral treatment (HIV). This theme involves a strong element of clinical research, notably in the context of multicentric trials and ANRS working groups, and is complemented by more fundamental research.

 Management team:

The Unit is directed by Berthe-Marie IMBERT who is PU-PH. A laboratory council has been established. The team deals with persistent viral infections (CMV, BKV, HIV and more recently HCV), host cellular responses and host genetic polymorphism. The overall relevance and originality of the research performed by this team is good.

There is a strong element of clinical research and a more fundamental research program, the most visible element being the analysis of KIR receptors. Although the local environment has played a role in different research themes, efforts to focus on a unifying research project will be helpful for the future structuralization of the team.

 Strengths and opportunities:

-Arrival of the HCV team to reinforce the fundamental research in Virology.

-Quality of the clinical trials. Strong and visible expertise in this field.

-Very good support of the EFS (2 full-time scientists, two technicians).

 Weaknesses and threats:

-Low impact of publication and lack of visibility in Virology.

-Insufficient external grants.

-Lack of patents regarding the applied research.

-Low number of PhD awarded.

-Too diffuse research programm (too many projects).

-Different location of the two groups that compose the unit.

 Recommendations:

-Focus on the most promising and visible projects in fundamental Virology.

-Improve the funding sources.

-Enroll more PhD students.

-Reinforce local collaborations related to human cellular immunology.

-Define a strategy to recruit, in the short/middle term, a full-time EPST scientist in fundamental Virology.

-"Accord cadre" EFS/University to be signed (intellectual property, etc.).

 Production results: Over the last three years, the quantity and the quality of the publications related to basic research are relatively low (11 publications, 7 with IF < 3 and 4 with IF 3-6 mostly on KIR receptors and NK alloreactivity including 1 J. Immunol. and 1 Eur. J. Immunol).

Joined publications with extramural collaborators (multicentric clinical studies) or related to "peripheral" clinical projects are numerous and of good quality (more than 40 publications including 2 J. Clin. Oncol., 1 Leukemia, 1 Clin. Infect. Dis., 2 AIDS and 4 J. AIDS). This denotes the dynamism and the strong relationships with the clinicians who compose the unit.

There is a lack of patent and of attempt to commercially exploit biological products derived from the research activities (e.g. specific KIR2D antibodies).

Two PhD students are currently in the unit. Three PhD theses and 2 HDR diplomas have been completed since 2008.

The unit is also strongly involved in clinical research based on local cohorts of infected/grafted patients. Three different clinical departments in Nantes Hotel-Dieu collaborate with EA4271. Members of the unit are also involved as principal investigators in several national (ANRS) and international multicentric studies. The quality of the networks in which the clinicians are involved is very good. In contrast, extramural collaborations related to basic/fundamental research projects are relatively low and could benefit from the local expertise in Immunology.

 Appreciation on the impact, the attractiveness of the research unit and of the quality of its links with international, national and local partners :

Invitations of PIs who compose the unit in international congresses are relatively scarce, thus denoting a lack of visibility of the research on the international scene. Clinical trials on HIV patients have raised a substantial number of grants from public organisations (PHRC, ANRS, European network). Although not detailed in the activity report, the team also benefits the contribution of private associations and pharmaceutical industries. It is noticed that no substantial grants for more fundamental projects (including ANR grants) have been obtained over the last three years.

The attractivity (high level scientists, foreigner post-docs) is small. Clinicians of the unit participate to national and international networks/clusters. Long term collaborations with some foreign, as well as local, clinician partners exist. Although announced, there is a clear lack of visible collaborations with local groups working in the field of Immunology.

The concrete results of the research are of clinical importance and might be valuable to better harness HIV infection and opportunistic viral infection following transplantation. The impact of the fundamental research is less obvious.

 Appreciation on the management and life of the research unit:

Despite its recent creation, it is noticed that interactions between clinicians and scientists (University / EFS) composing EA4271 appear to be strong. There is also a real will to optimize synergies between researchers of the unit and those from the group working on HCV that will be joining the group (see below). The proposal is intended to deal with the respective priorities of the hospital, university and EFS.

The strategy to promote the emergence of cutting edge projects is nevertheless not clearly defined. Attempts to improve the visibility in the field of virology is clearly annouced but awaits results. Due to its composition, the contribution of the staff members to teaching is high. The implication of the team leader in the structuration of the research at the local level is strong. The objective in the middle term is to integrate an Inserm unit/center but the plan to integrate such a structure remains to be defined.



  Date and execution of the visit :

(

  cf. http://www.aeres-evaluation.fr/IMG/pdf/Criteres_Identification_Ensgts-Chercheurs.pdf) A1: Number of permanent researchers with teaching duties (recorded in N1) who are active in research 7 A2: Number of permanent researchers without teaching duties (recorded in N2) who are active in research 10 A3: Ratio of members who are active in research among staff members [(A1 + A2)/(N1 + N2)] 1 A4: Number of HDR granted during the past 4 years 2 A5: Number of PhD granted during the past 4 years 2 3  Specific comments  Appreciation on the results: The questions addressed are mainly related to post-transplantation complications and are therefore of clinical relevance especially in the context of the local clinical/research activities developed in Nantes. Clinical trials on HIV patients are also of medical importance. Thus, the research themes developed by EA4271 have a potential high impact in health.

 Staff members (on the basis of the application file submitted to the AERES):

		Past	Future
	N1: Number of researchers with teaching duties (Form 2.1 of the application file)	5	6
	N2: Number of full time researchers from research organizations (Form 2.3 of the application file)	2	2
	N3: Number of other researchers including postdoctoral fellows (Form 2.2 and 2.4 of the application file)	8	5
	N4: Number of engineers, technicians and administrative staff with a tenured position (Form 2.5 of the application file)	5	7

N5: Number engineers, technicians and administrative staff without a tenured position (Form 2.6 of the application file) 1 N6: Number of Ph.D. students (Form 2.7 of the application file) 3 N7: Number of staff members with a HDR or a similar grade 5 6 5 2  Overall appreciation on the research unit  Summary:

Statistiques de notes globales par domaines scientifiques

	(État au 06/05/2011)

Sciences du Vivant et Environnement

	Note globale	SVE1_LS1_LS2	SVE1_LS3	SVE1_LS4	SVE1_LS5	SVE1_LS6	SVE1_LS7	SVE2 _LS3 *	SVE2_LS8 *	SVE2_LS9 *	Total
	A+	7	3	1	4	7	6		2		30
	A	27	1	13	20	21	26	2	12	23	145
	B	6	1	6	2	8	23	3	3	6	58
	C	1					4				5
	Non noté	1									1
	Total	42	5	20	26	36	59	5	17	29	239
	A+	16,7%	60,0%	5,0%	15,4%	19,4%	10,2%		11,8%		12,6%
	A	64,3%	20,0%	65,0%	76,9%	58,3%	44,1%	40,0%	70,6%	79,3%	60,7%
	B	14,3%	20,0%	30,0%	7,7%	22,2%	39,0%	60,0%	17,6%	20,7%	24,3%
	C	2,4%					6,8%				2,1%
	Non noté	2,4%									0,4%
	Total	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%
	*

les résultats SVE2 ne sont pas définitifs au 06/05/2011. Intitulés des domaines scientifiques Sciences du Vivant et Environnement • SVE1 Biologie, santé SVE1_LS1 Biologie moléculaire, Biologie structurale, Biochimie SVE1_LS2 Génétique, Génomique, Bioinformatique, Biologie des systèmes SVE1_LS3 Biologie cellulaire, Biologie du développement animal SVE1_LS4 Physiologie, Physiopathologie, Endocrinologie SVE1_LS5 Neurosciences SVE1_LS6 Immunologie, Infectiologie SVE1_LS7 Recherche clinique, Santé publique • SVE2 Ecologie, environnement SVE2_LS8 Evolution, Ecologie, Biologie de l'environnement SVE2_LS9 Sciences et technologies du vivant, Biotechnologie SVE2_LS3 Biologie cellulaire, Biologie du développement végétal

 Appreciation on the scientific strategy and the project:

Main modification will be the incorporation of a new group working in the field of Hepatitis C (HCV) infection (1 PU-PH, 2 technicians, 1 PhD student, 1 post-doc). The research activities of this group concern the variability of HCV and its relationship with cellular tropism and pathology. The team will be restructured into two groups (HIV/HCV and viruses/transplantation) to improve the synergy between lab members working on different projects within each theme (6 HDR).

The HIV/HCV group will maintain a strong element of clinical research and will develop fundamental research projects related to the consequences of virus genetic variability on the antiviral immune response, viral replication and tropism.

The Viruses/Transplantation group will conduct mechanistic studies and clinico-biological investigations.

As it states, the research program is too diffuse and sparse. There are too many separate/distinct projects without clear links between them. Clear choices should be taken to optimize the future impact of the research activities. Success in obtaining national (i.e. ANR) and international grants will rely on the ability of the scientific board to focus on the most competitive areas. The implantation of a unifying research project will aid to improve the visibility of the team.


Ms Danila Valmori

Roland Mr

Liblau

Ms Nathalie Chaput

Ms Clotilde Thery

Ms Paola Nistico

Maria-Pia Protti

Mr Antoine Toubert

Mr Jérôme Alexandre

Ana-Maria Lennon-Dumenil

Ms Christine Tufferau

Mr Regis Bataille

Jean-Michel Rogez

The site visit of the "Cancer vaccines and Immune regulation Team" took place over 2,5 hours on February 15th, 2010. The organization allowed the visit to go smoothly. The committee had enough time to listen to the presentations and discuss their scientific content, assess the research of the 2 groups, and discuss with the students around their posters and also in a more informal manner.

At the end, the review panels met to exchange their views and to organize the preparation of the final report.

 History and geographical localization of the research unit, and brief presentation of its field and scientific activities

The 2 PIs of the research unit moved to France from Columbia University Medical Center in New York in 2007. They have since established the first basic research laboratory in the Nantes Cancer Center. Initially associated with INSERM Unit 892 (CRCNA) located some 15 km away, the "Cancer vaccines and Immune regulation Team" has decided to develop an independent INSERM unit in order to increase the visibility of their cancer vaccine program. This decision has been taken with the full support of the acting Director of the Nantes-Angers Cancer Center. The research team remains closely associated with international programs and consortia, such as the Cancer Vaccine Collaborative and the Ludwig Institute for Cancer Research.

Their main field of activity is to develop active immunotherapy programs for cancer patients using cancer-testis antigens. This implies developping the immunomonitoring tools as well as in-depth investigation of qualitative aspects of the T cell reponse in humans, areas in which the team has invested major efforts during the last 4 years.

 Management team

As foreseen, the team will include 10 staff members (scientists, teaching scientitsts, clinicians, technicians and students). The unit is managed smoothly hand in hand by the 2 PIs. Given the small size of the unit at the present stage, the financial and administrative management of the team goes without problems.

The trainees have easy to access to the 2 PIs and communication is fluid among the team members. Concerning scientific animation, internal laboratory meetings are organized on a weekly basis. These include journal clubs given by students and post-docs. As scientific seminars are very rarely organized at the Cancer Center, the trainees are encouraged to participate to national or international congresses or to attend the IFR seminar series. 2 Overall appreciation on the research unit

 Staff members

 Summary

The team researchers presented an ambitious and very well structured program on cancer vaccines and immune regulation. Since they moved to Nantes in 2007, they were able to set a laboratory that is fully equipped with state of the art instruments for cellular and molecular immunology. For development of their program they recruited a good number of technicians, PhD students and post-docs and they also have planned further recruitments in the near future. The scientific approach and data presented are solid and sound. The research already produced a large number of high-quality publications and a patent. The program is very well funded both nationally and internationally. The location of the laboratory within the Cancer Center favours interactions with clinical and surgical oncologists essential for both preclinical and clinical studies. These collaborations add to others previously established both national and international. In addition, the future attraction within the Cancer Center (as already planned by the Director) of other research units will increase, the opportunities for daily basis interactions with researchers of the same or other fields of interest, especially for PhD students and post-docs.

 Strengths and opportunities

 Weaknesses and threats

The main weakness is related to the isolation of this research team in the Cancer Center of Nantes. There is therefore an urgent need for the Cancer Center and Biomedical research authorities to increase its critical mass of scientists and further help this excellent team to recruit new staff ranging from technicians to researchers.

 Recommendations to the head of the research unit

Encourage the PhD students and post-docs to interact with other scientists, especially those from other immunology and cancer research Laboratories in Nantes. This could be readily initiated by facilitating their attendance to seminars organized by these distant laboratories.

 Production results

3

 Appreciation on the impact, the attractiveness of the research unit and of the quality of its links with international, national and local partners

The team researchers presented an ambitious and very well structured program on cancer vaccines and immune regulation. Since they moved to Nantes in 2007, the 2 co-PIs have secured prestigious positions (PU-PH and DR with AVENIR contract).

They were able to set a laboratory that is fully equipped with state of the art instruments for cellular and molecular immunology. They have trained 1 post-doctoral fellow, 2 PhD students and 3 M2R students. Currently, 2 post-doctoral fellows, 1 PhD student and 2 assistant-engineers are being trained in the laboratory. Space is available for further recruitments.

The program is very well funded both nationally (ARC, INCa, Fondation de France, Région) and internationally (Ludwig Institute for Cancer Research, Cancer Research Institute, FEDER).

They have been invited to 14 lectures at international Workshop or Congress.

Their main field of activity is to develop active immunotherapy programs for cancer patients using cancer-testis antigens. The impact of the research, albeit hypothetical at this stage, may be considerable.

 Appreciation on the strategy, management and life of the research unit

Without revealing specific research aims, the overall goal of the team is to follow up their studies on the spontaneous and the vaccine-induced T cell reponses to tumor antigens in cancer patients. In parallel, in-depth investigation of the relationship between Treg cells and other CD4 T cell subsets will be pursued and investigation of the specificity of Tregs cells present at the tumor site performed. These studies should lead in the very near future to early phase clinical trials in patients with ovarian cancer or breast cancer.

The potential of these studies in terms of implementation of new anti-cancer vaccines approches associated with refined immunomonitoring is real. Identification of subsets of cancer patients with an immune repertoire allowing efficacious anti-tumor immunotherapy is an additional potential outcome of these studies.

Given the clinical environment, the accumulated know-how, and the international networks they are associated to, the feasibility of the projects presented by the 2 PIs appears solid.

The two PIs seem to synergize perfectly. The technicians, engineers and students are blooming and happy in the team. Management is harmonious with discussion and consensus decisions. There is however an urgent need for the Cancer Center and Biomedical research authorities to increase its critical mass of scientists and further help this excellent team to recruit new staff.

 Appreciation on the project

The general project on cancer vaccines and immune regulation is ambitious and very well structured. Most projects are in line with their previous work. However, new and cutting edge projects, in particular related to the lineage relationship between Tregs and other functional subsets of CD4 T cells, have emerged and will be actively pursued.

Several projects are developped in highly competitive fields but high gain is expected.



  Date and execution of the visit

   Specific comments  Appreciation on the resultsBetween 2006 and 2010, several articles published every year (with one of the 2 PIs as last author) in journals such as Clinical Immunology, Cancer Immunol Immunotherapy, or Journal of Immunotherapy (IF 3-4), plus at least one article in journals of higher impact factor such as J Immunol or Clinical Cancer Research, IF 6-7, or PNAS: IF 10. One patent has been filed on the NY-ESO1 immunodominant epitopes.The team performs very strong translational research regarding NY-ESO1 in cancer patients and the rationale to use this antigen as a therapeutic cancer vaccine in cancer-bearing patients. More specifically, they have shown that vaccination using recombinant NY-ESO1 protein elicits a good CD8 T cell response in 50% of vaccinated patients, with HLA-B35 and/or -Cw3 positive individuals exhibiting more consistent responses. The CD4 T cell response against NY-ESO1 was also studied using, in particular, original His-tagged peptides/HLA-DR tetramers as investifgation tools. The helpful developpment of such immunomonitoring tools should lead in the near future to great clinical research studies on the natural adaptive CD4+ immune responses in cancer patients.Very strong more basic science for Th17 differentiation and lineage plasticity in humans and on Treg cells. In particular the team has identified human natural naive Treg cells based on CD25 and CD45RA markers. They went on to dissect the FoxP3+ T reg population and identify central memory and effector memory subsets. Interestingly, they identified a human memory Treg subpopulation that secretes IL-17 and expresses ROR t. Natural naive FoxP3 Treg A1: Number of permanent researchers with teaching duties (recorded in N1) who are active in research 1 A2: Number of permanent researchers without teaching duties (recorded in N2) who are active in research 1 A3: Ratio of members who are active in research among staff members [(A1 + A2)/(N1 + N2)] 1 A4: Number of HDR granted during the past 4 years 2 A5: Number of PhD granted during the past 4 years 0 cells do not produce IL-17 but can be induced by cytokine cocktails including IL-1 to acquire ROR t, produce IL-17 and down-regulate FoxP3. These very original data document, using human cells, the great plasticity that exists within the CD4 compartment and open wide possibilities in terms of manipulation of the CD4 functional subsets.

Sciences du Vivant et Environnement

		Intitulé UR / équipe IMMUNOREGULATION VACCINS ANTI-CANCER ET		C1 Statistiques de notes globales par domaines scientifiques C2 C3 C4 Note globale A+ A+ A A+ A+ (État au 06/05/2011)
	C1	Qualité scientifique et production Note globale SVE1_LS1_LS2	SVE1_LS3	SVE1_LS4	SVE1_LS5	SVE1_LS6	SVE1_LS7	SVE2 _LS3 *	SVE2_LS8 *	SVE2_LS9 *	Total
	C2	A+ Rayonnement et attractivité, intégration dans l'environnement 7 3 1 A 27 1 13	4 20	7 21	6 26	2	2 12	23	30 145
	C3	B Gouvernance et vie du laboratoire 6 C 1	1	6		2	8	23 4	3	3	6	58 5
	C4	Non noté Stratégie et projet scientifique 1 Total 42		5	20		26	36	59	5	17	29	1 239
		A+	16,7%		60,0%	5,0%		15,4%	19,4%	10,2%		11,8%	12,6%
		A	64,3%		20,0%	65,0%		76,9%	58,3%	44,1%	40,0%	70,6%	79,3%	60,7%
		B	14,3%		20,0%	30,0%		7,7%	22,2%	39,0%	60,0%	17,6%	20,7%	24,3%
		C	2,4%							6,8%		2,1%
		Non noté	2,4%									0,4%
		Total	100,0%		100,0%	100,0%		100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%
	*

les résultats SVE2 ne sont pas définitifs au 06/05/2011. Intitulés des domaines scientifiques Sciences du Vivant et Environnement • SVE1 Biologie, santé SVE1_LS1 Biologie moléculaire, Biologie structurale, Biochimie SVE1_LS2 Génétique, Génomique, Bioinformatique, Biologie des systèmes SVE1_LS3 Biologie cellulaire, Biologie du développement animal SVE1_LS4 Physiologie, Physiopathologie, Endocrinologie SVE1_LS5 Neurosciences SVE1_LS6 Immunologie, Infectiologie SVE1_LS7 Recherche clinique, Santé publique • SVE2 Ecologie, environnement SVE2_LS8 Evolution, Ecologie, Biologie de l'environnement SVE2_LS9 Sciences et technologies du vivant, Biotechnologie SVE2_LS3 Biologie cellulaire, Biologie du développement végétal


Mr Jean

Luc Duroux

Ms Françoise Nepveu

Pierre Mr

Legrain

Serge Mr

Verdeyme

 History and geographical localization of the research unit, and brief presentation of its field and scientific activities

The research group entitled " Biomolécules et thérapies anti-tumorales" was created in 2006 and got the label " EA-4021" in 2008. This laboratory was formed by the grouping of several research units of the Faculty of Pharmacy at Limoges. The Univeristy researchers ("enseignants-chercheurs") are biophysicians, chemists and biologists developping research projects in the field of pharmacochemistry of natural products with antitumoral activities.

The research group is localized in the building where all the teaching and research activities of the Faculty of Pharmacy are concentrated. The surface on which the research unit works is important, about 980 m2. The experimental and office rooms are distributed on two levels.

Three main scientific fields are developped by the research unit:  Theoretical chemistry: molecular modelisation and quantic chemistry;  Phytochemistry : polyphenolic compounds and redox mechanisms;  Apoptosis and cellular differenciation: metabolism of arachidonic acid and cellular signalisation.

 Management team

The research group is managed by Jean Luc DUROUX who is also responsible of a research axis and recently elected Dean of the Faculty of Pharmacy. In theoretical chemistry, the studies mostly relate to the reactivity of specific groups during synthesis using Density Functional Theory (DFT) methods. This is used to rationalize chemical reactions and improve synthesis rates. This was also applied more specifically, coupled to experimental studies on natural molecules such as flavonoids. Together, these studies allow to make some prediction for antioxydant properties of new compounds.

On the apoptosis and differentiation projects, the focus was made on the use of natural compounds, ursolic acid and diosgenin, a triterpene and a plant steroid, respectively, for the induction of apoptosis in cancer cell lines. The results indicate a role of the expression of COX-2 gene for the resistance to apoptosis.

The general assessment of the research unit is very contrasted, with positive points (1) the dynamism, the cohesion and the efforts of the whole staff to go towards a true interdisciplinarity, characterize this unit which is strongly supported by the Regional Authorities; (2) All the University researchers are very strongly implicated in many sectors of teaching and take a good care of their PhDs students. It is to be noticed that this research unit does not host any full time researcher from EPST; and concerns about the scientific strategy (1) the multiplicity of the research topics mainly in biology, does not support the interdisciplinarity posted in spite of the methodological and conceptual expertise of the University researchers and (2) the integration of University researchers, wanted and encouraged by the Presidency of the University is another factor of dispersion.

 Strengths and opportunities

-Association of competences in theoretical chemistry, phytochemistry and cellular biology; -Sets of themes with the interface chemistry-biology; -The good state of mind of the various personels : French doctorants and foreigners are proud to belong to this research unit; -The will to increase the quality of the publications. The impact factor of their publications increased during the precedent four-year plan (close to 3 in 2010); -A good match for the research actions supported by the Région Limousin.

-A possible opening (even an association) to a laboratory of the University working in the field of the natural substances (EA-1069).

-Recruitment of young University researchers following the retirement of several seniors. The future research topics of these new recruited scientists constitute a challenge.

 Weaknesses and threats -Dispersion of all topics which alters the coherence of the project in spite of an acceptable assessment on the subjects concerning theoretical chemistry; -Difficulty to find a scientific positioning; subjects developped in phytochemistry and in cancer biology, in particular, being very competitive; -No national financial support (failure of two requests to the ANR), and international in spite of the integration of the group "theoretical chemistry" in an European network COST;

 Recommendations

The Committee recommends a significant effort of concentration of the different themes by selecting one or two niches allowing identification natural bioactive molecules that would allow biologists to identify and to use them as tools for studying mechanisms (intracellular and molecular) of cancerogenesis or inflammation. The committee considers as interesting the work in theoretical chemistry but the group must be integrated in the biological set of themes which will be developed. The Committee recommends to strengthen the links with the other laboratories of chemistry (in particular) which develop the same or complementary activities.

It can be understood that university teams are under pressure from their academic authorities to welcome publishing scientists from various horizons, in order to have all publishing scientists and MD's of the university being affiliated to a recognized research team. But, by doing so, they are at risk to be unable to define a clear scientific strategy and to compete properly at the international level. If the goal is to put researchers together to continue publishing at a modest level and to train students and allow them to pass PhDs, this strategy can still work. But, if the goal is to develop an original and promising research on a well chosen scientific niche, to increase the scientific visibility of the university, then the strategy has to be deeply re-envisioned. The members of the Committee noted a different level of information between the document received before the day of audit and the slides presented, those being much more complete.

 Production results

A1

The fields of the research unit may be summarized as following: (1) Extraction of natural flavonoic compounds, studies of their capacity to scavenge free radicals with experimental and theoritical methods in order to establish correlations to predict their biological properties; (2) Studies of the effects of some polyphenols (diosgenin) on the apoptosis process or on the cellular differenciation mechanisms on some cancer cell models.

However if in each one of these fields some original results were obtained, the general orientation as well as the interdisciplinary of the work does not appear.

Thus the interdisciplinarity put ahead by the members of the research unit did not appear and represented rather a juxtaposition of competences.

The unit produced, between 2006 and 2010, 60 publications with an average impact factor in 2010 of 3.01. This production for 15 University researchers leads to an average of 4 publications (ACL) per University researcher. This is a good performance.

They mentioned two invited conferences, fourteen oral communications and eleven posters. This oral production in national and international congresses is very low. Seven thesis of university were defended (for 14 HDR) and two HDR. The PhD students originate from several foreign countries.

The partnership with the Conseil Régional Limousin is very good. There is no currently valorization of the work with industrial partners.

 Appreciation on the impact, the attractiveness of the research unit and of the quality of its links with international, national and local partners Distinctions or awards have not been reported for the permanent members of the laboratory.

Two conferences were presented.

The diverse origins of the PhD students in term of nationality show the capacity of the Research Unit to accommodate students supported by the Région Limousin. Training of the students in research is made under excellent conditions.

It is surprising that the research unit does not take part in the activity of the Pole de Compétitivité du Grand sud-Ouest (Cancer-Biology-Health).

The budget of the unit relies strongly on regional and local support (42% Conseil Régional; 37% MEN; …). This reflects the good insertion of the laboratory in the regional environment However, the weak budget of the unit limits its influence.

The participation in international programs is limited to an European project COST. Attempts were made at the ANR level without success.

The research unit is well integrated on a regional level: financial support, PhD fellowships.

 Appreciation on the management and life of the research unit

After reading the document, the committee's experts had the impression that no integrated picture of the activities of the different teams was provided. Nevertheless an important effort was made during the oral presentations by the three speakers. Regular seminars are held by the researchers of the different groups.

The fifteen University researchers of the EA-4021 are much involved in the local university formation mainly in the sector "pharmacie". All of them are over-loaded in hours of teaching and duties that prevent them to concentrate on research as they would like.

 Appreciation on the scientific strategy and the project Dispersion of the themes decreases the relevance of the project in spite of the will of the various actors. The interface between chemistry-biology is not optimized because of the lack of a common goal.

The Committee strongly encourages the research unit and its actors to work out a new project, in particular within the framework of a process of fusion with the EA-1069 whose activities are closely related to their own. This would allow the unit to reach a size that would permit the development of competitive projects.

The allocated funding and basic supports remain weak and make difficult a policy of attribution of resources and scientific encouragement.

In spite of some original results obtained by each set of themes, the Committee recommends to the unit to set up a project integrating all the scientific actors of the unit which would contribute to a better national visibility and their integration into national and international programs. The quality of young University researchers makes feasible such an approach.

 Appreciation project by project

Project 1: Theoretical chemistry and molecular modelisation

 Appreciation on the results

Molecular modeling as a tool to understand and predict chemical and biological properties of natural compounds are carried out in the group of theoretical chemistry which is composed of three University researchers, since several years. The calculation of physic-chemical parameters (descriptors), (e.g., bond dissociation enthalpy, electron transfer capacity, acidity, spin densities) result in excellent correlations between experimental data and calculated values. The demonstration done on free radical scavenging properties of many polyphenols is convincing. These results make it possible to explain the kinetics of transfer of the electrons in the reactions implied between antioxidants and radicals and to predict certain biological properties (antioxidant properties, anti-inflammatory drugs, inhibition of enzymes LOX and COX, anti-proliferative effects). This work led to 7 publications in very good journals of the field and allowed the opening of collaborations with several national teams and European (Tchequie, Spain, Belgium) like with Malaysia. The quality of the results made it possible to the team to be integrated in a co-operation European project in science and Technology (COST 0804 -Chemical biology with natural compounds). This shows the expert testimony of the team in the field of quantum chemistry applied under investigation properties of natural products.

 Appreciation on the scientific strategy and the project

The project of the team is directed towards the study of the trapping of the free radicals formed during the lipidic peroxidation and the capacity of natural antioxidant molecules (polyphenols) to approach the cellular membranes and to be anchored to them. The team proposes to explore molecular architectures polyphenol-cellular membrane by using the processes of molecular simulation of dynamics to study molecular assemblies made up of several thousands of atoms. The project is original and based on a know-how acquired for several years and is complementary to other approaches, carried out in particular within the program COST in which the team knew to be integrated. Thus the team has a scientific niche.

 Conclusion

 Summary

The team showed its expert testimony in the field of theoretical chemistry and molecular modeling. The process of molecular modeling made it possible to obtain very good correlations between the properties (antioxidant) of polyphenols and the computed values. Although the study of the antioxidant properties of polyphenols were already studied and modelled by various approaches, the processes of calculation implemented by the team are original. The team acquired an European notoriety by integrating a COST program "Chemical biology with natural compounds". The chance to work with a Finnish group having complementary approaches is now given to the team. The Finnish approach (studies of docking between proteins and natural substances) and approaches of the team of Limoges (molecular architectures of natural substances and cellular membranes) must be used as support with the construction of a joint project to obtain financing by the EC.

 Recommendations

The Committee recommends to the team to strenghen collaborations already established and to integrate international programs in order to raise high scientific level and increase financial supports.

The team showed its capacity to predict the antioxidant properties of natural substances with these modelisation tools and its original approach. The group must now apply them to originale molecules, natural or synthetic, discovered whenever possible by the other teams of the laboratory.

Project 2: Experimental chemistry

 Appreciation on the results

The report mentioned no assessment on the chemistry of synthesis and extractive chemistry. On the other hand the oral presentation showed the good will of the researchers involved in the development of this field. A new young University researcher was recently integrated in this set of themes.

 Appreciation on the scientific strategy and the project

The project presented in chemistry of synthesis in order to obtain molecules with anti-inflammatory drug activity (inhibiting of COX-2/5-LOX) and with antioxidant activities by pharmacomodulation of the flavonoïde skeleton (quercetin) is certainly interesting but public and private international competition is very strong in this field.

The project presented in lichen phytochemistry is very original but the number of scientists assigned to this objective is very limited.

 Conclusion

 Summary

The pharmacomulation of quercetin and the fractionation of extracts of lichens constitute the principal activities of this group.

 Strengths and opportunities

Knowledge and expertise in chemistry of synthesis and phytochemistry are appreciated. The integration of a young researcher in phytochemistry is positive. The presence of biologists and chemists in computationnal chemistry is an asset for the discovery of bioactives molecules that indeed requires strategies at the interface chemistry-biology.

 Weaknesses and threats

The human resource on this theme of chemistry of synthesis and phytochemistry is very limited compared to international competition in this field.

 Recommendations

The Committee recommends to this group of chemists to focus, for example, on the original molecules extracted from lichens in order to discover new pharmacophores on which physicochemical modeling could be carried out while connecting them to the biological activities controlled by the group.

The process of collaboration-fusion with the EA 1069 presented at the time of the audit should be made profitable to increase their potential in human resource and scientific effectiveness.

Project 3 : Apoptose et Différenciation

 Appreciation on the results

The activity of the group has been focused on the study of the effects of various natural compounds (ursolic acid and vegetal steroids) on differentiation and apoptosis of several cellular models. Classical methods were used to characterize differentiation and apoptosis and to explore the pathways involved. A specific attention was paid to the connection of these effects with the modulation of expression and activity of Cox-2. The work, rather descriptive, included also mechanistic approaches using pharmacological modulators and siRNA. The most interesting result is the demonstration that Cox-2 is induced by the natural agents used and counteracts their pro-apoptotic effect in cancer cells. The association of coxib's with proapoptotic anticancer drugs could therefore be of interest. However, in vivo confirmation is missing.

Another interesting observation, was that the molecules used were stimulating terminal differentiation at low concentrations and apoptosis at higher concentrations in erythroleukaemia cells, a phenomenon already reported by others with different pro-apoptotic agents inducing terminal differentiation involving death pathways in different cell types, including keratinocytes and erythrocytes. However, the pro-apoptotic concentrations appear quite high (20 microM) and can be a concern for potential medicinal applications, if envisioned. Here again, in vivo confirmation is needed. The ability to trigger differentiation by low doses of pro-apoptotic agents is of fundamental interest and identification of the pathways involved (apoptotic pathway stimulated at low level, other pathways?) is recommended Members of the team have also a true competence in the field of HHV-6, however this part is not developed in the document and just mentioned in the project.

The group developed good and productive collaboration with another local team of the same federative institute specialized in cell fractionation using the FFF technique (Field Flow Fractionation). However, links of this group with the rest of the team (molecular modeling and medicinal chemistry) appear limited, with no common papers.

From the 60 publications listed for the 2006-2010 period in the report of the team, 43 (72%) are related to biology and clinics. Among them, 26 have a first and/or last author from the team and the rest corresponds to collaborative work done with teams of the federative institute of research in Limoges. The two main topics covered by the original publications of the team are the exploration of the effects of ursolic acid and vegetal steroids on differentiation/apoptosis of various cellular models (10 papers plus 4 in collaboration with a local team) and characterization of HHV-6 virus in human pathologies (8 papers), with a specific focus on Hodgkin lymphoma. Publications appeared in specialized journals with impact factor around 3 and some above 4 (Apoptosis, Int J Cancer, Clin Cancer Res).

The group had a good training activity, with 5 PhD and 2 HDR and 5 PhD in preparation.

 Appreciation on the scientific strategy and the project

The team intends to develop three different projects: (1) A main broad project on apoptosis and differentiation including three sub-projects: (i) in vivo evaluation of the effects of the biomolecules already largely studied in vitro by the team (ursolic acid and diosgenin, (ii) study of the effects of these molecules on hematopoietic stem cells and (iii) study of the role of cyclooxygenase 2 in differentiation and apoptosis of megacaryocytes. (2) A project to explore the pathways responsible for the effects of the product of the DR7 gene of Human Herpes Virus type 6 (HHV-6B) on cell proliferation, and its relation to cancer, in particular Hodgkin lymphoma, (3) A project to explore the effects of tocilizumab, an anti IL6 Receptor antibody, on the production of anti-inflammatory lipidic mediators by human synoviocytes.

These two last new projects are very isolated compared to the principal project on apoptosis and differentiation.

A weak point is the lack of one common scientific question addressed by the team, and not enough scientists dedicated to each project, even if each of them is of scientific interest. With such a strategy, it will be difficult for the team to increase the level of its publications.

 Summary

True expertise of the group. Decent scientific activity, with a modest, but slowly improving mean impact factor of papers. The project is not focused and the strategy should be re-evaluated.

 Strengths and opportunities

The team has a good potential and a real expertise in the exploration of apoptosis and differentiation in several cellular models. The interaction with medicinal chemists is an asset to study the effects and the mechanism of action of original promising molecules.

 Weaknesses and threats

Articulation with the priorities of the medicinal chemistry group is not clear. There are too many and too ambitious projects for a small team.. No focus on one major scientific question. Developping an in vivo model for testing molecules cannot constitute by itself a scientifc objective.

 Recommendations

The committee strongly recommends to select a topic on which the team has a chance to contribute in an original way. To develop a true integrated approach with medicinal chemists. The question of the role of Cox-2 in the control of apoptosis in the context of the use of pro-apoptotic anticancer drugs is extremly interesting, although highly competitive.

An effort should be made to increase the impact of publications. This implies again a more focused approach, deeper mechanistic studies and validation using animal models.



  Date and execution of the visit The evaluation took place on December the 2nd , 2010 in Limoges at the Faculty of Pharmacy, part of the University of Limoges. The welcome of the members of the Committee and the organisation of the day were excellent. The visit was made according the following agenda:  Conversation behind closed doors between members of the Committee to remember the rules of the valuation made by the AERES scientific advisor;  Presentation of AERES and aims of the evaluation in front of all research unit members;  Research unit Director presentation (report and project of the research unit)  Scientific presentation by the three group leaders of the research unit;  Meeting with each category of personnels (searchers, PhD students, IATOS);  Interview with the Vice-president of the scientific Committee of the University of Limoges, the Director of IFR-GIEST in presence of the Director of the valorisation ;  Discussion behind closed doors between the Committee members.

  engineers, technicians and administrative staff without a tenured position (Form 2.6 of the application file) 0 N6: Number of Ph.D. students (Form 2.7 of the application file) 7 N7: Number of staff members with a HDR or a similar grade 9 14 2  Overall appreciation on the research unit  Summary Several results have been obtained in the laboratory during the last four years in the different areas research.



  : Number of permanent researchers with teaching duties (recorded in N1) who are active in research 14 A2: Number of permanent researchers without teaching duties (recorded in N2) who are active in research 0 A3: Ratio of members who are active in research among staff members [Appreciation on the results

Sciences du Vivant et Environnement

	Note globale	SVE1_LS1_LS2	SVE1_LS3	SVE1_LS4	SVE1_LS5	SVE1_LS6	SVE1_LS7	SVE2 _LS3 *	SVE2_LS8 *	SVE2_LS9 *	Total
	A+	7	3	1	4	7	6		2		30
	A	27	1	13	20	21	26	2	12	23	145
	B	6	1	6	2	8	23	3	3	6	58
	C	1					4				5
	Non noté	1									1
	Total	42	5	20	26	36	59	5	17	29	239
	A+	16,7%	60,0%	5,0%	15,4%	19,4%	10,2%		11,8%		12,6%
	A	64,3%	20,0%	65,0%	76,9%	58,3%	44,1%	40,0%	70,6%	79,3%	60,7%
	B	14,3%	20,0%	30,0%	7,7%	22,2%	39,0%	60,0%	17,6%	20,7%	24,3%
	C	2,4%					6,8%				2,1%
	Non noté	2,4%									0,4%
	Total	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%
	*
	Intitulé UR / équipe	C1	C2	C3	C4	Note globale
	CHIMIE DES BIOMOLÉCULES, SIGNALISATION ET PROCESSUS CANCÉREUX	B	B	C	C	C
	C1 Qualité scientifique et production
	C2 Rayonnement et attractivité, intégration dans l'environnement

C3 Gouvernance et vie du laboratoire C4 Stratégie et projet scientifique Statistiques de notes globales par domaines scientifiques (État au 06/05/2011)

les résultats SVE2 ne sont pas définitifs au 06/05/2011. Intitulés des domaines scientifiques Sciences du Vivant et Environnement • SVE1 Biologie, santé SVE1_LS1 Biologie moléculaire, Biologie structurale, Biochimie SVE1_LS2 Génétique, Génomique, Bioinformatique, Biologie des systèmes SVE1_LS3 Biologie cellulaire, Biologie du développement animal SVE1_LS4 Physiologie, Physiopathologie, Endocrinologie SVE1_LS5 Neurosciences SVE1_LS6 Immunologie, Infectiologie SVE1_LS7 Recherche clinique, Santé publique • SVE2 Ecologie, environnement SVE2_LS8 Evolution, Ecologie, Biologie de l'environnement SVE2_LS9 Sciences et technologies du vivant, Biotechnologie SVE2_LS3 Biologie cellulaire, Biologie du développement végétal