Mr Marc

Etienne Meyer

MAZOYER, CYCERON, Caen Mr Bernard

CERMEP, Lyon Mr Gérard Gimenez

Ms Valérie

Mr Pierre Legrain

M Saïd Kamel

Traitement de l'Image Dynamique et Applications Médicales

The team was visited on February 11, 2011. The committee met at 10 am and was first given presentation by the project leader, Mr. Meyer, followed by talks of the differents themes and sub-project leaders. Then researchers, the students & post-docs, and technical staff members, were interviewed in parallel by one member of the committee. A session gathering representatives of the University of Picardie, Amiens University Hospital, and the dean of the Amiens medical school followed, before the committee started its closed door meeting during which it established the main lines of its report. The meeting was adjurned at 4 pm.

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

The TIDAM team is currently labelled as a "research team" by the Amiens University. It gathers scientists from different clinical departments of the Amiens University Hospital, some of whom previously belonged to a former research unit, whose leader moved to Paris a couple years ago. The team is localized on two different sites, the MR team in the north hospital, and the PET team in the south hospital. The team has focused its research on some methodological aspects both in MRI, namely quantifying the CSF flow, and quantifying portal venous flow, and in PET, in the area of motion correction reconstruction algorithm. Clinical research based on these methodological developments are in progress in the field of high intracranial pressure (MRI), and plexus choroid energy metabolism and liver cancer (PET).

 Management team

The team is currently managed by Mr. Etienne Meyer, head of the Nuclear Medicine department of the Amiens University Hospital. He is a nuclear physician with heavy teaching and clinical duties. Its past scientific achievements place him in a medium range of the national community in the field of medical imaging. There seems to be presently no particular management structure or strategy in the team, the two separate MRI and PET groups running their activities in parallel. This is the first application and evaluation of this team for an « Equipe d'accueil (EA) » label. The team benefits from some highly motivated young personel, and is receiving strong support of both the hospital and the University. However, its scientific program was found to be of limited ambition and originality, and its management to be questionnable. Overall, the committee judged the project, as it stands, likely to have very limited impact in the biomedical research field.

 Staff members

 Strenghts and opportunities

The team is certainly benefiting of the presence of two young and highly motivated scientists and from the dynamism of its technical personnel. It is strongly supported 1) by the Hospital Clinical research Director, who happens to be a member of the team, 2) by the Picardie University, that expressed its interest in developing image processing as one of its research theme, and 3) by the of the school of Medicine, who is also a member of the team. The team is expected to move altogether in a new building in the south hospital, which should considerably help in improving the internal unit dynamics in scientific exchange. In its direct environment, the team should consider the "Faire faces" project as an opportunity to start high level collaborations with this newly nationally labelled project (EquipEx). The partnership between the Picardie University and the Technological University of Compiègne (UTC) also offers interesting opportunities for major scientific collaborations.

 Weaknesses and threats

The fact that the team is constituted of two groups located in two different sites is certainly a concern, that could be overcome if the entire team moves in the new building of the south hospital. But the committee judged that a more serious concern was the fact that the team appears to be constituted of two subgroups with very little if any scientific exchanges between them. In addition, the committee found that the scientific projects proposed by both groups were marginally innovative, being merely the continuation of ongoing projects. In the very competitive field of medical imaging techniques development and applications to clinical research, the committee found very surprising the absence of projects based on perfusion imaging on the MRI side, as well as the lack of strategy for obtaining radiopharmaceuticals other than FDG. As it stands, the project appears as a collection of clinical research protocols, some of which being the continuation of ongoing projects, with no methodological research per se. The collective limited scientific ambition is already apparent in the past publication record of the team members who have no publications in the leading medical imaging journals in the fields of PET and MRI. They also exhibit very few invited lectures abroad, and no awards. The committee also pointed out that the project is threatened by the intrinsic difficulties attached to the running and development of a methodology oriented research unit in a University Hospital environment. The committee was particularly concerned with the unlikelihood that additional tenure positions in the field of medical imaging technology could be offered to scientists who do not hold a medical degree. Finally the committee also pinpointed the lack of a clear strategy for diffusing out and/or protecting and commercializing its methodological work.

 Recommendations

As it stands, the project needs to be deeply reorganized and resubmitted after the addition of new projects of higher scientific quality and originality in the field of medical image processing. This might require the appointment of a different team leader, dedicated full-time to federate and stimulate the PET and MRI groups, and having the capacity to establish strong collaborations with methodological research teams outside the University Hospital. The new project should integrate developments in MR based perfusion and diffusion imaging, and projects based on a true multimodal imaging approach. With this respect, collaborations with another local team doing research in neonatalogy with EEG are strongly encouraged. The new project leader should also exhibit a strong determination in searching collaborative projects with the "Faire Faces" team. Overall, the committee judged that TIDAM research projetcs in the past five years were only marginally original and had a limited impact on the scientific/medical communities. The MRI flow methodology project mostly consisted in implementing standard pulse sequences. The evaluation of the clinical importance of estimating the CSF flow in intracranial hypertension is still undergoing within the framework of a multicentre study. Besides, although original, the FDG studies of the choroid plexus energy metabolism seems of limited potential interest. As for the PET reconstruction method project, several algorithms for accounting motion in the image reconstruction process have been published since many years, and the work of the TIDAM team in this field is more a refinement of work published by other teams than a true genuine contribution. Evaluation of this algorithm for the detection of liver tumours is also undergoing. During the 2005-2010 period, the five TIDAM researchers have published 17 articles in peer-reviewed journals with impact factor (IF), including one in Eur J Nucl Med en 2008 (IF=4.2), and 2 in J Cereb Blood Flow Metab (IF=5.4) in 2007 and 2009. The other articles appeared in journals such as J Neuroradiol, JMRI, AJNR, Acta Radiol, Nucl Med Com that do not belong to the top list in the field of medical imaging, their impact factors ranging from 0.4 to 3.2. Six theses have been produced by TIDAM, among which 3 did not end with a publication. The main partnerships of TIDAM are with the clinical departments of Amiens University Hospital and have been established several years ago. TIDAM has also one on-going partnership with Cambrige University on the topic of intracranial pressure measurement.

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

This research unit has not yet reach national recognition, either as a team or at the individual researcher level. Staff members have not been granted awards worth mentioning, and have received a limited number of mostly local or national invitations for lectures. TIDAM mostly gathers local university hospital professors and MD's. However, the unit has recently hired on an assistant professor tenure position a longlasting member of the team in charge of MR methods. There is also a good chance that the scientist in charge of PET methods will be hired in the near future on a similar kind of position. Both are young dynamic scientists who exhibited the will to develop TIDAM. TIDAM unit record does not mention the recruitment of permanent personel from abroad. However, it is worth mentioning that a vietnamese PhD student recently joined the team thanks to a grant from his government. The team has been quite efficient in raising money to conduct his research protocols. Most of this funding comes from clinical research protocols (Programme Hospitalier de Recherche Clinique), but almost never from highly competitive sources such as ANR, INCA or EU. However, TIDAM has received some funding for its collaboration with the Cambridge University in the domain of intracranial pressure assessment, the only longterm collaboration in which the team is engaged.

 Appreciation on the management and life of the research unit

The unit project is currently organized along two main themes, each associated with a geographical location and a preferred imaging technology. The proposed management was very much in line with the current one, lacking dynamism and innovative ideas for bringing together the two components of the unit and promoting cutting edge projects. Overall, it was clear that the proposed project is lacking both a clear scientific leadership and a management capable of gathering all team members. However, during the visit, the committee could detect among the project leaders and the personnel a clear ambition to build a more ambitious project with one leader fully dedicated and involved in the research protocols.

 Appreciation on the scientific strategy and the project As it stands, the project unfortunately lacks a long term scientific strategy. With rare exceptions, such as the Alzheimer protocol, it is for the most part a continuation of ongoing protocols, and the overall project follows the dichotomous organization and management that has prevailed over the past four years. Actually, it looks like as if the project has been built without any prior in depth analysis of the most recent literature on the topics that the team has been working on. As a consequence, the proposed research lacks originality and risk-taking and it is hard to identify any cutting edge project. Methodological developments in MRI are quasi absent in the proposed project, the MRI project mostly consists in pursuing and completing the multicentre study on high intracranial pressure, although it is worth mentioning that the team is willing to establish a collaboration with physicists of Compiègne Technology university in order to design and build a physical model of the cranio-rachidian system. On the PET side, again proposed methodological developments are limited both in originality and potential applications. As for clinical research with PET, besides continuing the liver tumour protocols, the team presented a new protocol on plexus choroid metabolism disturbance as a potential origin of Alzheimer disease, but the grounds on which this protocol is built did not appear very firm.



  Date and execution of the visit



  Production results A1: Number of permanent researchers with teaching duties (recorded in N1) who are active in research 5 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 1 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%
	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
	TRAITEMENT DE L'IMAGE DYNAMIQUE ET APPLICATIONS MÉDICALES: TIDAM	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

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 Jean-

Pierre Marolleau

Elizabeth Mrs

Macintyre

Hélène Mrs

Coppin

M David

M François-Loïc

M Patrice Cacoub

Christine Mrs

Tuffereau

Visit took place on February 9th, 2011. The proposed director made a general introduction on the team and the future projects that were more extensively presented by senior researchers from the team. Some posters were presented by PhD students. After close-doors meeting with the University and Inserm representatives, the committee met researchers, students and technicians in the absence of the proposed director. Evaluation ended with a closed-doors meeting of the jury.

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

The unit was created in 2003, under the direction of M. Kaiss LASSOUED and is located within the Faculty of Medecine at Amiens. Its historical interests were early B lymphoid development and signalling, prinicipally via the pre-B Cell Receptor (BCR) and via STAT5. Renewal of the unit as a single-team is requested by M. Jean-Pierre MAROLLEAU, with four projects based on analysis of normal and pathological B and T lymphocytes and their roles in lymphoid oncogenesis.

 Management team

The director is M. Jean-Pierre MAROLLEAU. 2  Overall appreciation on the research unit

 Summary

The historical research themes of the unit were signalling through the pre-BCR, the function and expression of ZAP70 in normal and leukemic B cells and the role of TGF-beta and STAT in precursor B cells. These were essentially led by two researchers who both left the unit in 2008. Four subsequent projects have been developed including :

-Analysis of atypical Immunoglobulin (Ig) kappa rearrangements;

-The potential role of the SLAM family CD229 receptor in Hepatitis C Viral infection of B lymphocytes;

-Analysis of the innate immunity of human Mucosal Associated Invariant T lymphocytes and their non-classical MR1 receptor;

-Assessment of the potential for reprogramming from B lymphocytes in chronic lymphocytic leukemia to plasma cells in myeloma.

The role of the past director in the proposed future program was not clear from the documents submitted for evaluation prior to the site visit and was not clarified during the visit.

 Strenghts and opportunities

The arrival of a PU-PH and an MCU-PH/Avenir in 2005, followed by one MCF (CNU65) in 2006 and one PU-PH and two MCU-PH in 2008 has led to a significant reinforcement of teacher-researchers in Immunology, Cell Biology, Genetics and Hematology, in compensation for the loss of the EPST researchers. The proposal to progressively identify common research themes both within the proposed research group and between neighbouring groups on the Amiens campus is to be encouraged. The functional immunological aspects of HCV infection of mature B lymphocytes, potentially in synergy with the EA4294 team is one such example. The involvement of the proposed new director in a large number of national cooperative clinical studies is likely to help progressive integration of the research teams in appropriate translational projects, as cited during the presentations of individual researchers during the visit.

 Weaknesses and threats

There is clearly a problem with the transmission from the previous to the proposed director. The previous 4-year mandate was presented neither by the past director nor his proposed successor and the past director was not present during the audition of tenured scientists, despite the fact that he still appears to be part of the proposed research team.

The strong local academic support for tenured posts and post-doctoral positions is out of balance with the absence of full time researchers and has not led to the attribution of competitive national funding other than one Avenir program awarded in 2007, nor to an appropriate number and level of publication. The four proposed projects have little inherent inter-relationship, as described prior to and during the site visit. In keeping with this, there is a low number of co-publications by members of the research unit.

The new director plans to play a predominantly managerial role, in keeping with significant clinical responsabilities in hematology, oncology and cell therapy, including involvement in the recently awarded EQUIPEX "FIGURES". This may further contribute to the pre-existing dispersion, despite a very convincing desire to become involved with the unit during the presentation at the site visit.

 Recommendations

-The long list of manuscripts cited as being in preparation should be submitted and published.

-The role of the ex-director should be clarified.

-The unit must focalise its research themes in order to become more competitive and needs to undergo fundamental restructuring in order to ensure collaboration between the individual teacher/scientists.

-The SLAM/CD229 project, once published, should be explored in a synergic fashion with both the hematology/oncology expertise in mature B lymphoid malignancies within the unit and with the neighbouring EA4249 team.

-The atypical Ig kappa rearrangement project should be redirected from immature to mature B lymphoid malignancies, in order to reinforce the CLL/myeloma reprogramming project. There is also significant scope for use of the existing immunogenetic expertise in application to the understanding mature B lymphoid oncogenesis.

-The cell therapy background and expertise of the proposed new unit director should be considered as a potential basis for futur project development at the immunology interface. As a specific example, the MAIT project might be explored within the context of mucosal grafting. Alternatively, the role of these cells in non-malignant disorders such as rheumatoid arthritis should be explored with the relevant clinical teams on the Amiens Campus.

 Production results

 Specific comments  Appreciation on the results

In total, 17 publications are cited, of which 11 have an IF>5. Six of these were published with ex-members of the unit as first or last author (Biochem J., Haematologica, Blood, Oncogene, J. Biol.Chem) and the remaining correspond to collaborative publications in reviews with intermediate IF (Leukemia, PloS Biol, J. Immunol.).

No comment can be made on the ongoing pre-BCR and B lymphocyte signal transduction projects of Team 1, led by the previous director, since these were described exceedingly succinctly in the written documents and were not presented during the site visit.

The SLAM/CD229 and MAIT projects are promising, but the limited data presented and, particularly, published is worrying. Notably, of the four future projects presented, only one (MAIT) has benefitted from previous publication on the subject.

Four students obtained a PhD thesis during the 2007-10 period, but it is noteworthy that all four were on the STAT5 theme, which was not presented.

Two members of the group gave one invited talk each and the ex-director gave three, all at national meetings.

The aforementioned significant changes in the constitution of the unit make evidence of partnership stability a weakness rather than a strength.  Appreciation on the impact, the attractiveness of the research unit and of the quality of its links with international, national and local partners

No mention was made of invitations to international conferences or symposia.

No mention of participation to national or international networks or collaboration with foreign academic laboratories was made.

No mention was made about socio-economic partnerships.

No foreign scientist, post-doctoral researcher or student was recruited. This is clearly problematic at both the national and international level.

During 2008 and 2009 one ANR (total 60 k€) and one AVENIR (90 k€) were obtained. For 2011, only one research contract has been obtained (AOL) and two others requested. No participation to scientific or industrial clusters was mentioned in the written documents, but the cell therapy participation (not one of the cited team projects) in the EQUIPEX "FIGURES" project was mentioned during the site visit.

 Appreciation on the management and life of the research unit

The apparent lack of transition from the past to the proposed management was striking. The proposed future management is heavily dependent on the ability of the three young MCU/MCU-PH to develop competitive research under the direction of a director with a declared coordinating role but with heavy clinical duties.

It is to be hoped that the proposed projects will lead to appropriate publications, which might make grant awards easier to obtain.

The large number of locally funded university appointments should ensure adequate availability of teachers. The cited transfer of one post-doctoral fellow (PhD obtained in the research unit) directly to DCEM3 medical training is somewhat surprising.

 Appreciation on the scientific strategy and the project

The team should concentrate their efforts on one or, maximally, two projects, based on published data. Despite the lack of publication and the succinct presentations, the panel considers that efforts should be concentrated on the MAIT/MR1 and the CD229/mature B lymphocyte projects.

Allocation of ressources will be determined by initial (CD229) or continued (MAIT) publication.



  Date and execution of the visit

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 0 A3: Ratio of members who are active in research among staff members [(A1 + A2)/(N1 + N2)] 0.87 A4: Number of HDR granted during the past 4 years 2 A5: Number of PhD granted during the past 4 years 4

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%
		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
	DÉVELOPPEMENT DU LYMPHOCYTE NORMAL
	ET PATHOLOGIQUE : TRANSDUCTION DES	B	A	Non noté	B	B
		VOIES DE SIGNALISATION
	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


M François

M Nicolas Glaichenhaus

The visit was organized on September 20th, 2011. It started with a general presentation by the head of the unit and was followed by several presentations by other lab members. The committee members then met with members of the research unit.

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

The project application relies on gathering clinical and biological expertises on multifactorial disorders to build a very large biobank (aiming at the follow-up of 100,000 individuals belonging to families affected by RA) for local and national projects studying the interactions between genetic and environmental risk factors. The members of the research unit do not have a dedicated lab space yet. They are clinicians and scientists from the university hospital of Clermont-Ferrand and the university of Auvergne.

• Management team M. François CORNELIS and Ms. Isabelle CREVEAUX are the co-heads of the research unit. The unit includes a total of 4 PU-PH, 1 MCU-PH, 3 CCA, 3 PH, 1 PhD student, 1 ARC and 2 administrative assistants including 1 for the communication. 2  Overall appreciation on the research unit

• Summary

The present project aims at conducting a follow-up in France of 100,000 individuals belonging to families affected with Rheumatoid Arthritis to (i) provide RA family members a predictive risk estimation for RA occurrence, (ii) discover novel genetic and environmental risk factors for RA, and (iii) use such cohort as prototype to study other multifactorial disorders that represent a major public health burden.

• Strengths and opportunities

• The major impact of a such project collecting sequencially biological samples from RA relatives is to provide researchers with biological materials from healthy donors that will develop RA (1/1000/year) to test any pathophysiological hypothesis.

• The medical and scientific relevance of the proposed approach is to identify (i) predictive risk factors for rheumatoid arthritis and (ii) molecular and cellular mechanisms associated with disease occurrence ;

• The ability of the two PI to build a project gathering researchers coming from different disciplines;

• The know-how of the two PI to organize the collection of biological samples ;

• The track record of one of the two PI in rheumatoid arthritis ;

• The strong links with Nutrinet, GenHotel Evry, and other international institutions ;

• The long-lasting support from the Association Française de Polyarthrite ;

• The research project focuses on two of the priorities of the university of Auvergne, i.e. genetics and nutrition ;

• The added value of this research unit for the local stakeholders including the Region Auvergne.

• Weaknesses and threats

• The success of the project will be highly dependent on a strong and long-lasting support from the local and national organizations (positions for technicians and engineers, lab space, long term sample storage, sample analysis…) ;

• Threat : the existence of other national and international cohorts focusing on rheumatoid arthritis or other inflammatory diseases.

• Recommendations

• Establish a clear-cut management policy, more specifically for ressource allocations ;

• Put some effort on the collection of samples from identical twins discordant for RA ;

• Recruit PhD students and postdoctoral fellows. 3  Specific comments

• Appreciation on the results

The head of the lab is the coordinator of a European network that has contributed to the identification of susceptible genes for rheumatoid arthritis. The analyzed "RA relative cohort" included 10,000 individuals. In this population, the incidence is 1/1,000 per year as compared to 1 /10,000 in the overall family. In the project, the goal is to expand the cohort to 100,000 individuals (of note, there are about 4 million potential participants in France).

During the past 5 years, the members of the lab have published more than 120 papers in peer-review journals including several as first or last author. Among the most important publications in first or last author are: 1 paper in The New England Journal of Medicine (2007), 2 papers in JAMA (2009,2010), 1 paper in PNAS ( 2007), 1 in Ann Rheum Dis (2008), 1 in Arthritis Rheum (2008). The scientific production is heterogeneous.

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

The members of the research unit are participants to several national and international organizations.

During the past 4 years, the research unit members have been able to raise significant funds including 230 k€ from the EU, 260 k€ from various associations, 18 k€ from the industry, 315 k€ from PHRC and 118 k€ from other sources.

The research unit has developed strong links with Nutrinet and the GenHotel Evry, and the Geneva University Hospital for the recruitment of individuals. Strong links have also been developed with local, national and international structures for the analysis of the samples. These include the Centre de Ressources Biologiques, the CHU biochemistry platforms, Ultra high through put sequencing, the GenHotel Evry, the CNG-CEPH, the Karolinska Institute…

• Appreciation on the management and life of the research unit

The project of the research unit is dependent on the recruitment of 100,000 individuals. Therefore, the research unit has developed a very efficient external communication policy with several partners including local newspapers, other media, and French pharmacists and rheumatologists.

Lab meetings have been organized on a weekly basis to construct the project. Among lab members, 5 have teaching duties and participate to the Master "Génétique et Physiology" at the University of Auvergne, the Master "Génétique" of the University Paris 7, the Master "Biologie Ostéo-articulaire" of the Universities Paris 7 and Paris 13.

• Appreciation on the scientific strategy and the project

The project is based on the recruitment of individuals who have at least one relative with rheumatoid arthritis. The objectives are (1) to document in these individuals the development of not only rheumatoid arthritis (RA), but also renal failure, anaphylaxis, birth-defect, venous thrombo-embolism (2) investigate genetic and environmental factors involved in disease onset including nutrition, smoking, infections and psychology. The specific aims are (1) to measure risk of known factors, (2) to search for new risk factors, (3) to search for biomarkers predictive of onset and (4) to identify new drug targets.

The "100,000 RA relative cohort" will be recruited mainly by the research unit in Clermont-Ferrand but also by Nutrinet-Santé, the GenHotel Evry and the Geneva CHUV. The recruitment procedure includes internet preinclusion, informed content sent by post, diagnosis confirmation by post, internet questionnaire, biological sampling and storage.

This ambitious project is highly relevant for public health and the research unit is well positioned to be successful. In the long term, this project may lead to the improved care of patients with rheumatoid arthritis, and possibly other diseases. This project could therefore have a major impact in the medical and scientific field. However, the success of the project will be highly dependent on a strong, secured, and long-lasting support for local and national organizations (positions for technicians and engineers, lab space, long term sample storage, sample analysis…).

•

  Date and execution of the visit

•

  Production results A1: Number of permanent researchers with teaching duties (recorded in N1) who are active in research 5 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)] 5 A4: Number of HDR granted during the past 4 years (Form 2.10 of the application file) NR A5: Number of PhD granted during the past 4 years (Form 2.9 of the application file) NR

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%
	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
	GenHotel-Auvergne	A	B	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

GenHotel Déterminisme multifactoriel de maladies aiguës/chroniques et de malformations congénitales Faculté de Médecine de l'Université d'Auvergne

Reply to the AERES report on GenHotel-Auvergne, University of Clermont-Ferrand I

We thank the committee for its review and his very positive assessment.

We are grateful to the committee to have pointed out the expertise of the different members of the group and the originality of this project gathering researchers from different specialties.

We would like to add some comments regarding the report.

The representatives of the University were the vice-president Pierre-Charles ROMOND, in charge of innovation, development and entrepreneurship in the University, and Pierre CLAVELOU, vice-dean of the Medicine Faculty.

We appreciated very much the quality of the discussion with the committee and his very constructive recommendations, especially regarding the collection of samples from monozygotic twins who are discordant for rheumatoid arthritis (RA). We have added to the project a specific effort to recruit such twins. We clarify the management policy, in particular for resource allocations and aim at recruiting rapidly PhD students as well as post-doctoral fellows, as the lab space issue is about to be solved.

The committee mentioned some threats regarding the existence of other national and international collections focusing on RA. We answer that today, we are the only national research unit focusing on large scale family material for RA and unaffected relatives. Abroad, the research teams with a track record on large scale RA family material (> 1,000 families) are in Manchester and New York. Very recently, two groups started similar projects on RA relatives, in Denver and Geneva, both aiming at the much smaller scale of 2,000 relatives in the next few years. We have established a strong collaboration with the Geneva's group and together, we are the only concerted effort in Europe so far. Many other groups in France, Europe and internationally conduct cohorts focusing on RA (with no focus on their relatives).

It is clear that we need to develop rapidly our resource to keep the benefice of our early start,

GenHotel

in the likely case of some of those strong groups deciding to add a focus on un-affected RA relatives. The stronger we will be, the more we will build on the successful collaborations with many of those groups, to have them as partners with access to our biological material, rather than competitors.

The committee noticed that the major difficulties we will have to face are the lack of technicians and engineers, the absence of dedicated lab space and long-term sample storage.

We would like to mention that, despite these difficulties, we have started to work on this project with local goodwill, allowing us to get storage for 20 000 samples for DNA, serum and cells and to wait for equipment grants (local, national or international). Since the committee's visit, the rapid development of the local CRB (Centre de Ressources Biologiques) at the University Hospital has been confirmed, with sufficient space to accommodate the storage for the project and dedicated human resources (cf letter of the CRB coordinator, Pr Berger, enclosed). As far as lab space is concerned, our Dean will provide us with 50 m 2 to start. At his request, we submitted a plan aiming at the lab space indicated in our project of 300 m 2 by 2013. For strengthening the human resources, the negotiation for the critical position of assistant-professor "MCU" included in our project is under way with our Dean and our President, potential candidates being invited to apply.

We will pursue to actively request further help from the University and the CHU of Clermont-Ferrand, regarding the high relevance of our project for public health and its high potential impact in medical and scientific field, points highlighted by the committee.

21/10/2011

Isabelle Creveaux

François Cornélis


M Stephane Descamps

M Frédéric

M Robert

M Dominique

M Jacques

M Philippe Dulbecco

The Visiting Committee was held on February 15, 2011 and started at 9am. After a close-door meeting of the committee to recall the role of AERES and the visiting committee, the history and record of the unit was presented by Stephane DESCAMPS in one of the amphitheaters of the Faculty of Medicine in front of all the unit members. The three main axes of the unit's project were then presented. The committee has asked to visit the laboratories located at the Faculty of Medicine and also at the Department of the IUT (Department of Physical Measurements).

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

The unit was created in 2010 by the joining of a laboratory of clinical Pharmacy and Biotechnology, the Faculty of pharmacy CHU Clermont-Ferrand, two surgical teams (Orthopaedics and Gynaecology) CHU Clermont-Ferrand, the Laboratory of Physical Chemistry IUT de Cezeaux, Clermont-Ferrand and Le Puy en Velay and the Laboratory of cell cultures, Department of Haematology CHU Clermont-Ferrand. The activities of the unit are organized around three main axes as follows: (1) Stability of nano-structured surfaces in living systems, (2) Release and toxicity of nanostructured surfaces and (3) Functionalization of nano-structured surfaces.

 Management team

The research unit is managed by M. DESCAMPS and by M. AWITOR. This young team was established in the beginning of 2010 by the merging of four groups around the thematic of assessing the safety of nanomaterial surfaces used in different clinical fields. The unanimous supports of the university, the university hospital and the technological college (IUT) have allowed the two managers to achieve an initial scientific management plan. These efforts made possible initial scientific achievements with patents and publications.

 Staff members

 Strengths and opportunities

The scientific concept of the toxicity of nanomaterial surface and its influence on clinical problems was clearly identified and is shared by all members. This opportunity is well illustrated in the topic "releases of phthalates" from PVC tubing of infused solutions. The team investigated the coextruded devices (PVC associated with a layer of polyethylene) supposed to protect from release of phthalates. They showed that the deposition of titanium dioxide on the surface of the tubes decrease the leaching of plasticizers. They successfully deposited a patent on this topic. The enthusiasm that leads the group and the involvement of the leaders well supported by the researcher is a strong point. The multi-disciplinarity of the group is a strong point as it is difficult in France to gather in a single research unit, end users, biologists, chemists, medical doctor and pharmacists working on the same topic. The integration of such competences has to be reinforced.

 Weaknesses and threats

The geographical splitting of the groups between different cities, campuses and hospital is a weakness. To lead the three main axes of the project, the number of equivalent full time employees is limited as well as the time given by the two technical persons. For the moment, the financial support is quite low regarding the challenging tasks to achieve in the three main axes involving in particular in vivo experiments.

 Recommendations to the head of the research unit

Due to recent evolution of the scientific plan following the visit of AERES committee, the unit heads should rewrite a new more focused scientific plan. The huge task to manage such a team is time consuming and imply that the manager who is central to project has to be liberated at least partly from his clinical work and teaching duties. The team has to participate to consortium to response to national calls for proposal (ANR). The research is focused on nano-materials and the detailed investigations of their toxicological effects. These materials have huge potentials in further technological applications in the health sector, but obviously their toxicity has to be well characterized. This is an important point often neglected today. Therefore, the chosen research field is significant with a number of societal and economic issues.

 Production results

A1

This new team has achieved in one year the development of an original set of three approaches on nanostructured surfaces. In such a short period the team was able to patent one innovation and to start two PhD theses and will get two CIFRE fellowships. However at this stage their scientific contributions and their capacity to take the subject beyond the state of the art are not completely identified. Especially, a very detailed literature search should be conducted to be able to develop their research plan further.

The research project consists of three axes: stability of nanostructure in the living, released and toxicity of nanostructure surfaces, functionalization of nanostructures surfaces. The more advanced domain with promising results is the release of plasticizers. The chosen methodology to address the problem is pertinent and innovative.

The methodology for the two others axis has to be developed. The "Functionalization of nano-structured surfaces" is quite a competitive field with different chemical or electrochemical techniques developed. To build a sustainable and original project, the team has to bench mark their techniques to the existing methods.

In that aspect the committee recommends the constitution of a scientific advisory board with external members, specialists of the domains, as it was presented by the head of the unit. It would be already beneficial to involve consultants from industry.

Since the creation of the joined team an increase in the overall impact factor of their publications was noted. The publications are in well known journals of the concerned fields.

A strong support of the supporting authorities is noted and the creation of such an interdisciplinary lab is coherent with the politics of the university.

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

There are 14 invited lectures in the different field of research concerned. This is evidencing the international visibility of the leading researchers of the project in particular of the gynecological surgeon.

The team was built by gathering researchers of different fields on the campus of Clermont-Ferrand. The two PhD students with strong scientific background are highly motivated and even if they are working part time their contribution is very beneficial for this young team. The existing collaboration with international laboratories is increasing the visibility of the lab further.

They are already involved in one FP7 project and they were successful in attracting additional industrial supports. One member is in charge of the budget and external contracting and this is very positive regarding the organization of the team.

The team intends to respond to national (ANR) and international (EEC) calls in the next years.

The submission of a patent is a clear indication of the important valorization expected by the university hospital and university. This patent is linked to the "Pôle de compétitivité de plasturgie du Puy en Velay". The involvement of two industrial partners, attested by the two CIFFRE grants, is clearly showing the valorization prospective and the importance of economic issues.

The academic partnerships exist already with the department of Physics and Astronomy, University of Oklahoma; the Bristol Implant Research Centre, University of Bristol and the laboratory of Pharmaceutics, Biopharmaceutics and Hospital, University of Lille II.

The strongest collaboration is with the University of Oklahoma with frequent research staff exchange. The US group is developing nanoporous surfaces and is not at all involved in medical research leaving this task to be fulfilled by Biosenss.

 Appreciation on the management and life of the research unit

The co-direction of an 18 member team is surprising but is justified by the interdisciplinary character of the lab. The two directors are very dynamic and have a close relationship.

The scientific meetings are held once a month and almost all members assist despite the different geographical localization and the clinical activities.

The good relationship between the members whatever their origin is visible and a good repartition of duties was noted.

The two technical persons are well informed of the research strategy and are willing to increase their involvements and their times.

In fall of 2011 the team is organizing a national conference on nanostructured surfaces.

The members have important teaching duties in the master on biomedical technologies. They are also participating to external masters.

 Appreciation on the scientific strategy and the project

The project is clearly focused on nanostructured surface properties and toxicities that is a pertinent subject. Clinical issues were identified: inadequate responses of scar tissue in contact with devices, release of toxic compounds by medical devices. To answer these issues it is clear that physical chemists, cellular biologist, clinicians are needed.

The chosen topics and the problems to solve are fitting well with the size of the group.

The project is oriented towards three medical devices, gynecological implants, orthopedic implant and medical polymers. In all of these fields they have significant experiences; together with the well managed project planning the overall feasibility is great. This is already proven by the first patent deposited, which could potentially help them to establish links with industries and obtain additional funding.

There are other laboratories in France working in the domain of medical devices but this lab is one of the few focus on nanostructured surfaces and related toxicity. At this stage of the project the risk are limited because they have a strong knowledge in the fabrication of the nanostructures and they plan to use existing protocols to evaluate the toxicity of the surfaces. Cette remarque illustre les nombreuses missions effectivement portées par les Enseignants Chercheurs et Hospitalo-Universitaires dans le système français. Nous souhaitons d'une part améliorer cet aspect par la mise en place d'un emploi du temps hebdomadaire défini et récurrent de l'ensemble des membres du groupe, et en particulier des directeurs. Les activités spécifiques de recherche seront identifiées, en associant les différentes structures hospitalières et universitaires. D'autre part, la montée en puissance du budget de l'équipe au travers de réponses à appels d'offres devra nous permettre au cours du prochain plan quadriennal de financer un poste de technicien au sein de notre équipe.



  Date and execution of the visit

  : Number of permanent researchers with teaching duties (recorded in N1) who are active in research NA A2: Number of permanent researchers without teaching duties (recorded in N2) who are active in research NA A3: Ratio of members who are active in research among staff members [(A1 + A2)/(N1 + N2)] NA A4: Number of HDR granted during the past 4 years NA A5: Number of PhD granted during the past 4 years NA 3  Specific comments on the research unit  Appreciation on the results

  s_descamps@chu-clermontferrand.fr Objet: Réponses au rapport d'évaluation par l'AERES du Laboratoire C-Biosenss Monsieur le Président, Nous tenons dans un premier temps à vous remercier ainsi que l'ensemble des membres du Comité AERES et le coordinateur de l'Agence Jacques Haiech pour la qualité de la réunion d'évaluation qui s'est déroulée sur la journée du Mardi 15 Février 2011 et pour la pertinence des remarques faites dans le rapport d'évaluation fourni à l'issue de cette journée. Nous notons que le Comité a relevé que le développement du laboratoire s'appuie sur un projet «pertinent» (p.6), «adapté à la taille du groupe» (p.6) et renforcé par une organisation «multi disciplinaire» (p.4). Nous souhaitons commenter un certain nombre de points relatifs au rapport d'évaluation: P.4: «The geographical splitting of the group between different locations». Nous avons pleinement conscience de la difficulté engendrée par cet état de fait. La multidisciplinarité du groupe explique historiquement cette répartition. De nouveaux locaux destinés à notre équipe ont été alloués au début de cette année par les Facultés de Médecine et de Pharmacie. Ces locaux sont destinés à devenir le coeur du laboratoire. L'enthousiasme (identifié par le comité dans son rapport) des membres de l'équipe doit permettre d'amplifier un sentiment d'appartenance fort au laboratoire et favoriser la présence physique au sein de ces nouveaux locaux. P.4: «The number of ETP and technician is limited» et «has to be liberated at least partly from clinical work and teaching duties».

P. 4 :

 4 «The financial support is quite low regarding the challenging task» Comme nous l'avions présenté au Comité, cette faiblesse avait été identifiée en interne, expliquée par la jeunesse du groupe. La remarque confirme donc que la recherche de financement doit être une de nos tâches prioritaires cette année. Nous pouvons d'ailleurs préciser et que, depuis la visite d'évaluation il y a un mois et demi, nous avons déposé deux dossiers : un appel à projets « Nouveau Chercheur » auprès du conseil régional d'Auvergne et une demande de bourse auprès de la fondation « groupe Pasteur ». Nous avons par ailleurs bénéficié d'un budget de la part de l'Université d'Auvergne dès cette année. P.4: «due to recent evolution of the scientific plan following the visit of the commitee, the unit heads should rewrite a new more focused scientific plan». Nous prendrons en compte cette remarque faite par le comite et notamment en ce qui concerne le caractère concurrentiel (« competitive field »p. 5) de l'axe numéro trois. Nous vous prions d'agréer, Monsieur le Président, l'expression de notre considération distinguée Les directeurs, Stephane Descamps et Oscar-Komla Awitor

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%
	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
	C-BIOSENSS: CARACTÉRISATION ET
	SÉCURITÉ BIOLOGIQUE DES SURFACES	B	B	A+	A	B
	NANOSTRUCTURÉES
	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

		Clermont-Ferrand, le 06 Avril 2011
	Laboratoire C-BIOSENSS	Monsieur le Professeur Frédéric Cuisinier


Ms Frédérique Penault-Llorca

Pierre Mr

Brousset

Jacques Mr

Bonneterre

Thierry Mr

Petit

Ms Emmanuelle Genin

Paul Mr

Hofman

Mr Philippe Dulbecco

The visit was organized on 9 February 2011.

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

The different teams listed below worked independently in different places (CHU, Cancer Center Hospital, University of Auvergne. The ERTICa's team is the merge of scientists coming from four different existing UMRs (UMR990 INSERM and (LMGE) -UMR CNRS 6023) or EAs (EA3846 UdA and 4233 UdA). ERTICa is composed of researchers from several backgrounds: cytogeneticists, oncogeneticists, cellular and molecular biologists, biochemists, pathologists, and clinicians. The starting point is cancer, a primary concern in the university's effort (Université d'Auvergne) to develop a strong cancer research axis. They focused on breast cancer, the most frequent cancer in female and the major disease treated in the Centre Jean Perrin, a comprehensive cancer center. They have chosen to focus particularly on triple negative breast cancer (TNBC) which represents an unmet medical need, a cancer frequently linked to BRCA gene alteration, with genetic instability.

• Management team:

The Head of the research unit is Ms. Fréderique PENAULT-LLORCA. M. Jean-Yves BIGNON, M. Andrei TCHIRKOV and JM Jean-Marc NABHOLTZ are in charge of the Exploratory axis of TNBC patients and tumors, the axis on the cellular biology preclinical models study of BRCA1 fucntions, and the axis on Clinical Research, respectively. The ERTICa research unit is overall well structured, offering an opportunity to create a good synergy between existing local groups. The general direction of the project (early BC in particular BRCA-related) is highly competitive at national and international levels. It would be very risky to develop it without a very strong component of national and international collaboration. Frédérique PENAULT-LLORCA is an international opinion leader in breast pathology. JM NABHOLTZ is an international leader in drug development. The clinical network for collecting tumors in Clermont-Ferrand area seems well established. There is a great need to find new biomarkers that predict clinical response to treatment of BC. All tools for developing the project seem to be present (except for in vivo animal models). There is a strong support from the institution (University, Hospital, Cancer Center). The weakest part of this project is the level of the basic science which is not sufficiently competitive at national and international levels. The low level of the publications (impact factor and citation indexes) is a major weakness of a project in competitive fields such as DNA repair, genetics instability and high throughput sequencing. There are not enough strong working hypotheses and the presented hypotheses either lack novelty or are not competitive with regard to available expertise and publication records of the teams. In summary, there is a too diffuse spectrum of research hypotheses and projects with no real interaction between the different research subgroups. The general recommendation is to focus the project on biomarkers and drug development. This should be done by attracting new people (including students) with expertise and strong track records in DNA repair area.

• Strengths and opportunities

There is a great need to find new biomarkers (very competitive field). All tools for developing the project seem to be present (except for in vivo animal models). The clinical network for collecting tumors in Clermont-Ferrand and around area is well established. This initiative is strongly supported by the host institutions (University, Hospital, Cancer Center). Frédérique PENAULT-LLORCA is a national and international opinion leader in breast pathology. JM NABHOLTZ was the leader of a world-wide clinical investigator group and can be very active to recruit patients; even if there are many patients receiving neoadjuvant chemotherapy in Clermont-Ferrand, the number will not be enough to carry out an internationaly recognised scientific program; his connections with the pharmaceutical industry will be very useful to have innovative new drugs that will be studied in the neoadjuvant model ( biomarkers evaluated before treatment at the time of biopsy and after treatment at the time of surgery). It will be important for the funding of research too.

• Weaknesses and threats

The quality of the basic science is not sufficiently competitive at the national and international level. The average level of the manuscripts in terms of impact factor and citation indexes is low. This is a major weakness of the project suggesting that the different groups are not able to address the several issues on DNA repair, genetics instability and high throughput sequencing. The working hypotheses lack strength and novelty. There is a too diffuse spectrum of research hypotheses and projects. There are no real links between the different subgroups. It looks as if this group wants to study everything in the field of genetic instability beginning with triple negative breast cancer. The biobank is a cornestone of the activity and should be reinforced. Stronger national and international collaborations are required in this highly competitive field. The number of students is too low to achieve the different goals.

• Recommendations

Focus on biomarkers and drug development. Attract new people with strong expertise and track records in the DNA repair area. It is mandatory to focus on some projects in which the group is well recognised, the translational and clinical research. The applicants have to position the project in a background of external collaborations. Regular joint meetings for students are necessary. More students need to be recruited. The relevance and the originality of the research, the quality and the impact of the result: Strong track report of two unit members. This program is risky because of national and international competition. There is a great need to find new biomarkers that predict clinical response to treatments of BC.

The quality and the number of the publications, scientific communications, thesis and other outputs: Average level for basic science. Many collaborative studies but no real landmark papers in the field in high impact factor journals. The papers in JCO by the project leader are either collaborative (national cohorts) or outside the scope of this project (gastric cancers).

The quality and the stability of partnerships: Important partnerships with pharmaceutical companies are apparently ongoing.

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

The head of the unit is frequently invited in international meetings concerning clinical trials. JMN has also a very good track record in this field.

The ability to recruit high levels scientists, post-docs and students, and more particularly from abroad: No specific information was provided. This could be a weakness of the project.

The ability to raise funds, to successfully apply for competitive funding, and to participate to scientific and industrial clusters: The translational research is quite good and attracts fundings from pharmaceutical companies (FPL, JMN) but this not the case for the basic science (INCa, ANR, ARC, Ligue..)

The participation to international or national scientific networks, existence of stable collaborations with foreign partners: No precise information. The head of the unit is an expert in the field of breast cancer pathology.

The concrete results of the research activity and socio-economic partnerships: A couple of patents was filed.

• Appreciation on the management and life of the research unit

The contribution of the research unit staff members to teaching and to the structuration of the research at the local level: The students have no dedicated joint meetings

• Appreciation on the scientific strategy and the project We thank the committee for their remarks and recommendations. We want to take this opportunity to address some points raised by the committee.

1. Introduction : No remark on the introduction 2. Overall appreciation of the research unit

• Summary

The ERTICa research unit is overall well structured, ……………. It would be very risky to develop it without a very strong component of national and international collaboration.

We are aware that the area of triple negative breast cancer is highly competitive and it would be very risky to develop it without a very strong component of national and international collaboration.

Frédérique Penault-Llorca and Jean-Marc Nabholtz have developed a network of national and international collaborations providing the access to large cohorts of patients and discussions and exchanges around biomarkers. Yves-Jean Bignon also participates in a strong national network of oncogenetics departments. For basic research, we have already identified in the CLARA (our canceropole) a network of possible collaborations.

Other collaborations (national and international) will also be examined.

"The weakest part of this project is the level of the basic science which is not sufficiently competitive at national and international levels"

We are creating a new research team and decided to work in the field of triple negative breast cancer for different reasons:

-The topic: the unmet medical need and the emergence of new therapeutic options such as DNA repair and EGFR targeting, -A unifying topic: the triple negative breast cancer option was also the link between different skills of the merging teams, apart from clinical research and biomarkers: BRCA environment for the oncogenetic group, genetic instability (through telomere axis) and chromosomes interactions for the cytogenetic group, cellular biology, MDR phenotype (for which PARP inhibitors and EGFR targeted therapies have not yet been explored), and cell line models with controlled BRCA function.

-

Gathering skills: to perform theses studies, different technological tools are already available through the different teams merging in this new research unit: in vitro models, high-throughput sequencing, array CGH, methylome and transcriptome facilities, as well as more classical tissue-based biomarkers studies.

-Access to relevant tumor samples: the most important thing is that our group will have access to patients in clinical trials (large ancillary studies have been planned and material already collected in the EGFR clinical trials). We also have a retrospective collection of tumours treated by neoadjuvant approach and of patients with familial history of breast cancer, which will be useful in developing our hypotheses.

-Our pioneering and strong role in clinical research in EGFR targeting: our international advance in the field of EGFR targeting (two neo adjuvant clinical trials have been developed: one is now completed, the other has already recruited half of the patients) and our previous expertise in the EGFR biomarker field (from colorectal and lung cancer), So yes, we agree, that today the current state of basic science in the field of DNA repair is the group's weaker link, and might be considered as poor or unsufficient. Nevertheless, some members of the team have established expertise in DNA repair and DNA repair genetics that was not fully valorized in the dossier because the references antedate the 2006-2010 window requested. For instance Nancy Uhrhammer is coming from Richard Gatti (UCLA, Calidfornia, USA) worldwide known for his works on ATM gene. Furthermore, our originality is a strategy "from the bedside to the bench and back to the bedside". Our research will first be clinical research and not basic science. In this context, where all the necessary tools are available (according to the report), an axis of basic research could be developed and be competitive only in the second half of the quinquenal project, based on the first results from the translational studies.

Reply to the AERES report concerning the project of creation of a research unit ERTICa (Equipe de Recherche sur les Traitements

Individualisés du Cancer)

Management and choice of axis to develop on the theme of "biomarkers " will pave the way for the establishment of competitive basic research especially in the field of repair DNA and EGFR targeting.

Strengths and opportunities ... ; even if there are many patients receiving neoadjuvant chemotherapy in Clermont-Ferrand, the number will not be enough to carry out an internationally recognised scientific program;

The advantage of the neo adjuvant approach is that it is an excellent human in vivo model for tumor response (sensitivity and resistance). The answers are quick (maximum 6 to 8 months of treatment), and evaluation of the data for ancillary studies doesn't need large patient cohorts. The clinical trials that we have planned all involve networks of health care centers, either national (such as Unicancer, including 20 French comprehensive cancer centers), or international to ensure rapid recruitment and completion of the study. We recently completed a neo adjuvant trial (75 patients) for TNBC involving 13 centers in just one year, showing our ability to create networks and to enrol patients quickly in neoadjuvant clinical trials.

• Weaknesses and threats

The quality of the basic science is not sufficiently competitive at the national and international level. The average level of the manuscripts in terms of impact factor and citation indexes is low.

It is important here to stress the point that the teams have worked in different backgrounds and on separate and very different subjects. The creation of the ERTICa team will potentiate our ability to improve our research projects and publication levels. We do not plan, in the first part of our research program, do develop basic science hypothesis apart from the cellular models, and some specific genes for which we have some knowledge (in somatic but also germinal samples of patients from the trial and few controls), the majority of the studies will be pure biomarker development programs.

Taking the cumulated H index of the groups merging for ERTICa it is not so low and poor overall. *In this area, some members worked previously on non cancer or xenobiotics, the highest journals ranks are at 3. Nevertheless, past four years, two patents with international extension have been filed in this group. This is a major weakness of the project suggesting that the different groups are not able to address the several issues on DNA repair, genetics instability and high throughput sequencing. The working hypotheses lack strength and novelty.

High throughput sequencing « 454 Roche » platform got a recent national label IBISA in 2009 working for different other teams (mainly in Lyon) is not producing yet publications ; nevertheless two papers have been submitted in 2011, one on BRCA sequencing in breast and ovarian cancer, and the other one on deep sequencing of ovarian epithelial carcinomas, screening for therapeutic targets. This underlines our expertise with the recently acquired high throughput sequencer.

For N Uhrhammer, YJ Bignon and A Tchirkov, these additional selected references may be cited:

-Varon R, Gosse-Brun S, Bignon Y-J, Sperling K, Uhrhammer N. Nijmegen Breakage Syndrome gene (NBS1) is not the tumor suppressor gene at 8q21.3 involved in colorectal Carcinoma (CRC). Oncol. Rep. 9: 709-11, 2002.

-Uhrhammer N, Bay JO, Gosse-Brun S, Kwiatkowski F, Rio P, Daver A, Bignon YJ. Allelic imbalance at NBS1 is frequent in both proximal and distal colorectal carcinoma. Oncol. Rep. 7: 427-31, 2000.

-Bay JO, Uhrhammer N, Stoppa-Lyonnet D, Hall J. Role of the ATM gene in genetic predisposition to cancer.

Bull. Cancer 87: 29-34, 2000.

-Bay JO, Uhrhammer N, Pernin D, Presneau N, Tchirkov A, Vuillaume M, Laplace V, Grancho M, Verrelle P, Hall J, Bignon YJ. High incidence of cancer in a family segregating a mutation of the ATM gene: possible role of ATM heterozygosity in cancer. Hum. Mut.,14: 485-492, 1999. To facilitate experimentation concerning radio-biology, the "Pavirma" platform has recently been funded at the University Blaise Pascal, and is currently under construction. This platform will provide both an X-ray generator (before the end of 2011) and a neutron cannon (in 2012) for irradiation of cultures, materials, plants and small animals. Ms Uhrhammer and Pr Bignon have been involved with this project since its inception in 2007, and Mr Bidet joins them on the planning committee as the facility takes form. These ERTICa team members, and possibly others, will participate in the scientific committee overseeing the platform. Interactions with other committee members constitute a local network of DNA repair-related researchers (C. White, P. Vernet, S. Alziari...) and physicists (G. Montarou...). This developing platform was not previously mentioned.

There is a too diffuse spectrum of research hypotheses and projects. There are no real links between the different subgroups.

We will be able after gaining results from the clinical trials to focus our basic research on one or two basic research programs. We repeat that this is a new merger, and the links between the groups will deepen and broaden with time as we work together and share results and ideas. It looks as if this group wants to study everything in the field of genetic instability beginning with triple negative breast cancer. The biobank is a cornestone of the activity and should be reinforced. Stronger national and international collaborations are required in this highly competitive field. The number of students is too low to achieve the different goals. Our project does not "want(s) to study everything in the field of genetic instability beginning with triple negative breast cancer" ! First of all our research will be focused on the patients in clinical trials, and some controls (35 tumors from BRCA positive patients, and post chemotherapy patients without response to treatment, as one of the clinical trial planned is for non responders). Second, the clinical trials are either targeting EGFR or genetic instability (via some special design of chemotherapy and/or by adding PARP inhibitors).

• Recommendations

Focus on biomarkers and drug development.

We will clearly focus on drug development through biomarker studies and when necessary go to the bench to confirm some of the hypotheses. For the patients in clinical trials we will explore both germinal (focused on 30 genes) and somatic alterations, mainly concerning the EGFR pathway when relevant and DNA repair and telomere function. The results from aCGH will correlated with the germinal and biopathological alterations, aiming to find surrogate markers. For the other patients, they will be part of the IBCSG program and of other collaborative programs.

Attract new people with strong expertise and track records in the DNA repair area. We are a new team, not even created, so recruiting senior scientists is for the future, when our program is established. It will not be possible to attract a senior scientist so early in our project.

It is mandatory to focus on some projects in which the group is well recognised, the translational and clinical research. The applicants have to position the project in a background of external collaborations. Regular joint meetings for students are necessary. More students need to be recruited.

Our students come principally from two masters programs: "Génétique et Physiologie" et "Cancérologie et Nutrition" But as of 2012, we will add our own source of students through the new Master "Biomedical technology and biomedical specialty" (M1 & M2).

As the new ERTICa team develops and becomes known, additional doctoral students and post-doctoral researchers will be recruited. Regular meetings among these junior scientists are planned as part of their training.

Production results We have granted 16 PhDs during the last four years, and currently have 10 PhDs and five post docs in training. This number is not so low for 13 researchers with teaching and heavy clinical duties, and in absence of permanent researchers without teaching duties.

A1

3 Specific comments

Appreciation on the results

The relevance and the originality of the research, the quality and the impact of the result: Strong track report of two unit members. This program is risky because of national and international competition. There is a great need to find new biomarkers that predict clinical response to treatments of BC.

The quality and the number of the publications, scientific communications, thesis and other outputs : Average level for basic science. Many collaborative studies but no real landmark papers in the field in high impact factor journals. The papers in JCO by the project leader are either collaborative (national cohorts) or outside the scope of this project (gastric cancers).

The JCO papers are from large biomarkers studies or clinical trials conducted by the project leader, showing the experience in the field of breast cancer and also the networks. The other papers are not outside the field because the colorectal (JCO, Lancet Oncology, clinical cancer research), and lung studies are in the EGFR biomarker field, which is completely in the scope of the project. The gastric cancer papers are in fact international guidelines, showing the networks and the experience in biomarkers determination.

The quality and the stability of partnerships: Important partnerships with pharmaceutical companies are apparently ongoing. They are ongoing.

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

The ability to recruit high levels scientists, post-docs and students, and more particularly from abroad: No specific information was provided. This could be a weakness of the project.

•

  Date and execution of the visit :

•

  Production results A1: Number of permanent researchers with teaching duties (recorded in N1) who are active in research A2: Number of permanent researchers without teaching duties (recorded in N2) who are active in research 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 A5: Number of PhD granted during the past 4 years 3  Specific comments • Appreciation on the results

:

  Number of permanent researchers with teaching duties (recorded in N1) who are active in research 13 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 2 A5: Number of PhD granted during the past 4 years 16

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

  Yes for the biomarkers. Not for the basic research

	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
	ERTICA: EQUIPE DE RECHERCHE SUR
	LES TRAITEMENTS INDIVIDUALISÉS	B	B	Non noté	B	B
	DES CANCERS
	C1 Qualité scientifique et production
	C2 Rayonnement et attractivité, intégration dans l'environnement
	C3 Gouvernance et vie du laboratoire
	C4 Stratégie et projet scientifique

The existence, relevance and feasability of a long term (4 years) scientific project: Risky. No strong background in basic research, too low number of students.

The originality and existence of cutting edge projects:

Statistiques de notes globales par domaines scientifiques

(État au 06/05/2011)

Sciences du Vivant et Environnement

As part of the upcoming quadiennal plan, the University of Auvergne will open a new, two-year undifferentiated (Research and Professional) Master, entitled « Biomedical Technology », and including a Biomedical Diagnostics specialty. This specialty was developed by Mahchid Bamdad of the ERTICa team, and recruits biology students as well as interested medical doctors and pharmacists. Within this masters program, Frédérique Penault-Llorca, the director of ERTICa, is responsible for the M1 Anatomo-pathology module, and several team members will be involved in teaching. We will train medical students, in particular, oncologists, genetic counsellors and pathologists. For instance, for the pathologists, for 2 years we have one student per year, and we have already planned additional M2 students in 2011-2012 and in 2012-2013, on the TNBC subject and in collaboration with the Gustave Roussy Institute and the department of pathology in University of Sydney (Westmead hospital….).The principal laboratory on which the Biomedical Diagnostic module of this Master program depends is ERTICa, which facilitates the recruitment of doctoral students.

ERTICa members are also involved in teaching specific modules in other Master programs (notably Genetics and Physiology). We have a long tradition in the formation of students from abroad, often in the form of short (< 6 months) stages, for both basic science students and medical specialists. For example, between 2006 and 2010, the Bignon group hosted 11 foreign students from seven countries, at levels from Master to post-doctoral/postmedical studies, with two Chinese students staying a full year.

Name of the research unit: Equipe de

The ability to raise funds, to successfully apply for competitive funding, and to participate to scientific and industrial clusters: The translational research is quite good and attracts fundings from pharmaceutical companies (FPL, JMN) but this not the case for the basic science (INCa, ANR, ARC, Ligue..) The participation to international or national scientific networks, existence of stable collaborations with foreign partners: No precise information. The head of the unit is an expert in the field of breast cancer pathology. We participate to the IBCSG program The cytogenetic team is involved in the national network on array-CGH analysis (ACPA). Already developed earlier for the rest of the activities with a focus on DNA repair

Ability to raise funds for basic research

The concrete results of the research activity and socio-economic partnerships: A couple of patents were filed. Six international patents were filled Appreciation on the management and life of the research unit

The contribution of the research unit staff members to teaching and to the structuration of the research at the local level: The students have no dedicated joint meetings Since the start of our project, students from the different units have gotten to know each other (and also the different senior researchers) through the monthly journal club and a variety of research meetings such as the "Journée Scientifique Régionale de Cancérologie d'Auvergne". Additional regular meetings will be organized, and they will have a dedicated area at the university in the future team.

Appreciation of the scientific strategy and the project

The existence, relevance and feasability of a long term (4 years) scientific project: Risky. No strong background in basic research, too low number of students. The competition is high, but our originality is the choice of the clinical research on drug development as the core of the project. It is a truly multidisciplinary team. The tools are in place, the skills are real, collaborative axes through the CLARA and the different clinical and pathological networks are in place. The project is focused only on the clinical trials and the biomarker research (early response, resistance etc…). Collaborations are in place also locally with the metabolic imagers and radiation therapists. The tumor bank is well organized, and adapted to our clinical trials in terms of authorizations, labelization and consents.

The originality and existence of cutting edge projects: Yes for the biomarkers. Not for the basic research In the medium term, the basic research will be based on hypotheses derived from the clinical trial biomarker studies. We do not have the pretension to re-do studies performed at a larger scale and by large groups such as the IBCSG. Our strength is the access to the patients in our clinical trials.

Pr Frédérique Penault-Llorca, on behalf of the ERTICa group.