The president of AERES "signs[...], the evaluation reports, [

 Introduction

History and geographical location of the unit This single Team Unit project is in the continuity of the previous U775. The Unit is located at the "Centre Universitaire des Saints-Pères" but some MDs are also working in Hôpital Européen Georges Pompidou.

Management team

The proposed director, Mr Pierre LAURENT-PUIG, PUPH, is the current director of the Unit 775. He has a strong experience in team management, he is well recognized at the national and international level for his studies, and he has the support of all the members of the project.

Strengths and opportunities

This is a team with a clear goal on translational research. They have the expertise, the tools and the necessary biological resources to perform their projects.

They have made an important contribution by discovering the inefficiency of the anti-EGFR antibodies in patients carrying a mutation in the Kras in colon cancer. These results are of major clinical interest and are used in national and international recommendations to select responsive patients.

They have published 101 original papers (Lancet Oncol, Cancer Res, Clin Cancer Res, Blood, PNAS, Hum J Genet, Gut, Hepatology, etc), including 5 JCO (Mr Pierre LAURENT-PUIG was first or last author on 4 of them). Their papers have been cited more than 2450 times during the last 5 years.

An original projet on microfluidics, well integrated in the global project of the Unit, has started more than one year ago and is a great methodological opportunity for this team.

The team has developed valuable on-site inter-disciplinary collaborations (with mathematicians), thus providing original tools for data-mining.

Through their participation to national and european programs (CIT Ligue contre le Cancer; PETTAC-8), the team has a privileged access to large collections of annotated human samples and clinical data.

The group has an excellent activity of technology transfer assessed by 6 patents and a number of collaborations with private companies. They have a noticeable capacity to obtain fundings through public and private research contracts (more than 3 M€ over the last 4 years).

Weaknesses and threats

Although the projects on cancer and anticoagulants/immunosuppressors represent the natural evolution of the previous studies, attention should be paid for the next five-year period to keep the balance and complementarity between these subprojects within the single-team unit.

Although one MCU-PH obtained the HDR (habilitation to supervise research) during the last 4-year period, the number of HDR in the lab is still relatively low (5).

There is a lack of a defined recruitment strategy for full time researchers at the EPST (Inserm or CNRS).

12 of 20 technicians have temporary (CDD) contracts, which means that they will have to leave soon or be proposed a permanent contract. Also, two tenured technicians will retire over the next few years.

A MCU physicist has been recruited during the last years in relation with the development of the microfluidic project but, for career reasons, he intends to leave the University. This is a major risk for this aspect of the project. Some basic aspects of the project, particularly those involving miRNA, TWIST1, ER Stress and autophagy, are very competitive and will be studied in collaboration with different other partners. This could be a risk since these research topics are internationaly competitive. It is recommended to recruit specialists in the field.

Recommendations

A careful thought within the lab is needed to reinforce (with PhD or post doc students) the pharmacogenetics and immunosuppressive drugs subprojects, and/or priorize the main project on anticancer drugs.

The unit may consider enlarging its domains of competence in the field of molecular biology to be more independent in some of its highly competitive projects.

The unit should increase its capacity of supervising doctoral students by having other members passing their HDR.

The unit should set up a plan to prepare young researchers for the CNRS and/or INSERM full-time researcher carreer (and competition for admission).

The technical competences and workforce are fragile, owing to many temporary contracts and the close retirement of two tenured persons.

 Detailed assessments Assessment of scientific quality and outputs

This is a large group that is working on a broad spectrum of translational and fundamental scientific projects ranging from pharmacogenomics and genomics to the development of alternative therapeutic approaches and, more recently has been developing original nanotechnology approaches. This is one of the most prominent teams on pharmacogenomics at the French level. They have established several polymorphisms associated to the variability in the response to anticoagulants and immunosupressive drugs. They have participated to a collaborative initiative to develop a Chip containig 16000 polymorphisms and they are leading large prospective French and European projects on colon cancer through 5 multicenter cooperative groups, with the goal to predict individual patient response to the treaments. They are supported by the CIT program of "La Ligue contre le Cancer" to characterize colon cancer samples at genetic and transcriptomic levels, with the goal to classify as homogeneously as possible these patients in order to develop personalized treatments. In the last 4 years, they have made an important contribution by discovering the inefficiency of the anti-EGFR antibodies in colon cancer patients carrying a mutation in the Kras gene. These results are of major clinical interest and are currently used in national and international recommendations to select responsive patients.

Concerning the most fondamental projects, the team has developed an original strategy of gene therapy for lung tumors by transfecting both an improved mutant of the CYP2B6 enzyme named CYP2B6TM and NADPH reductase (RED), which sentizises to treatments with cyclophosphamide. The preclinical results using a lentiviral vector seems to be promising. The team has found a link between the activation of the EGF-dependent pathway with the activation of TWIST1 and bad prognosis in lung cancer. They have found an miRNA as a promising marker of sensitivity to anti-EGFR treatment in colon carcinoma. They have also found data about the obesogenic role of some ambient contaminants such as TCDD and MEHP. Finally, a direct link between the treatment with ciclosporin, TEM, ER stress and autophagy and its nephrotoxicity has been established. The team developed a kit that is presently commercialized by a company to detect the levels of 23 isoforms of human CYP by RT-PCR that can be used to determine the toxicity of compounds and drugs.

The team is developing new and original techniques, in particular through the recruitment of a CR1 who has skills in microfluidics.

The group has published 101 original papers, some in top-ranking journals, 39 reviews and 15 letters. Together, these works have been cited 2450 times. Remarkably, all these projects are very productive in terms of publications and some of these results have been protected by patents (6 during the last 5 years). All the members of the team have delivered constant high quality results. The papers were published in good journals (J Immunol,Cancer Res (x3), Clin Cancer Res (x2), Am J Gastro, Autophagy, Am J Transpl, Diabetes, Clin Pharmacol Ther (x2), J Proteome Res, J Thromb Haemostas, Cell Death Diff, Lab on Chip, Hum Mol Genet, Am J Kidney Dis, Int J Cancer (x6), Ann Oncol) to very good journals (PNAS,Blood,Gut (x2), Hepatology, J Hepatol, Ann Neurology), and some in even excellent journals in the field of clinical oncology (5 JCO, of which 4 as a first of last author, one Lancet Oncology in collaboration). They have presented their results in 69 international and 29 national scientific meetings since 2008.

The group has also an excellent activity of technology transfer assessed by 6 patents and an impressive number of collaborations with private companies such as Servier, Integragen, Sobios, Myriad genetics, Raindance technology.

Assessment of the unit's academic reputation and appeal

The group participates in several international Consortia and has organized scientific meetings. The citation level indicates the recognition of its visibility at the international level. Their seminal contribution to identifying the inefficiency to anti-EGFR antibodies in colon cancer patients carrying the Kras mutation is widely recognized.

Mr Pierre LAURENT-PUIG is recognized as an international expert and leader in the field of pharmacogenetics and cancer. He participates to several scientific committees in France (INCa, Ligue contre le Cancer, Fédération Ftrançaise de Cancérologie Digestive, FFCD).

Other members of the team also participate to scientific committees and have been involved in national programs of evaluation and strategic plans. Two scientists of the team are members of Inserm specialized scientific committees for the current 4-year period.

The team leader was invited to give conferences in 23 international and 31 national scientific meetings. The other team members attended 27 international and 24 national conferences as speakers.

The quality of the research conducted in this Unit led to a number of French and International external fundings.

Assessment of the unit's interaction with the social, economic and cultural environment

The team leader is the president of the PETACC08 clinical trial which includes 2400 patients, and participates in the project Biointelligence coordinated by Dassault Systems and supported by OSEO. Five team projects have been supported by ANR (about 1.4 M€) and nine by INCa/Canceropole Ile-de-France (about 900 k€). The team also have had 16 scientific collaborations that all resulted in publications, and industrial collaborations with Servier, Integragen, Sobios, Myriad Genetics and Raindance technologies, some of which also also gave rise to scientific publications. The group has also an excellent activity of technology transfer assessed by 6 patents. The team leader is head of the SIRIC for the project "Cancer Research and personalized medecine" that includes 22 research units and has been endowed with 7.5 M€.

Assessment of the unit's organisation and life

The laboratory space is 120 m 2 and an additional space of 140 m 2 , which is shared with the INSERM U747, 145 m 2 of offices and a rest room of 20 m 2 . The committee visited the laboratory and concluded that the team need more surface area for developing their current project. Concerning the organisation of the laboratory, no special problems were detected by the committee, the communication between people is easy, health and safety issues are taken into account, responsabilities are well defined, the council of the laboratory is meeting regularly.

All people, including researchers, technicians and students seem to be very happy to work in the laboratory. Mr Pierre LAURENT-PUIG is clearly "the leader" of this team.

The committee found that 12 over the 20 technicians are contracted and payed on their own research contracts. There are almost no post-doc and the leader is well aware of this problem.

The committee noticed a problem concerning the management of the numerous grants obtained by the lab that needs to be improved. The authorities acknowledged this problem and will try to resolve it.

Assessment of the unit's involvement in training through research

Within the Unit, 8 members are Professors or Assistant Professors, and their duties include teaching per status.

Good activity of training PhD students: 10 students have obtained their PhD degree over the last 4-year period, among them 7 are currently MCU-PH, PU, SUP or are working at the AP-HP, 2 are pursuing postdoctoral studies abroad and 1 continues with medical studies. 10 PhD students are currently trained in the lab. Members of the Unit have also participated to the training of 35 Master students.

Two foreign researchers (Israel, Brazil) have joined the lab for a training period of 8 months and 2 months, respectively.

Remarkably, all PhD students of the laboratory published from 1 to 21 papers during the last 4 years period, with a median of 7 papers, which is really exceptional.

Team members are the national coordinators of the master 2 degree (M2) in "Toxicologie humaine, evaluations des risques, vigilances"; coordinators of 2 teaching units (UE) into the M1 of biology: "Metabolisme des xenobiotiques et implications en pharmacocinetique et toxicologie; immunologie, genetique et médicaments"; they participate in the organisation of "Ecole thematique analyse du genome tumoral"; they are members of the "conseil scientifique et bureau de l'ED Médicament"; finally, they are the coordinators of the "module biologie fondamentale IFSI Paris Descartes".

Assessment of the five-year plan and strategy

The project is entitled "Medicine Personalisée, Pharmacogénomique, Optimisation Thérapeutique" (MEPPOT). In general the project is the continuation of previous works.

Part 1 of the project aims at understanding : i)

the pharmacogenomics of the resistance to anticoagulants (anti-Vitamin K and new oral anticoagulants) ;

ii) the pharmacogenomics or nephrotoxicity of immunosuppressors (role of ER stress in calcineurin nephrotocixity, development of an algorithm for thiopurins dose optimization and identification of specific markers by candidate genes and RNA pan-expression analysis);

iii) the mechanisms of resistance to anticancer drugs (miRNA has-mir31-3p associated to ERGFR resistance, identification of minor cellular subgroups in 3-wt (Kras, Nras and Braf) tumors by "PCR in droplets").

Part 2 aims i/ to understand the role of cytochromes p450 on the metabolism of inhibitors of tyrosine kinases and ii/ to understand the role of reactivation of TWIST1 (EMT activation) expression in lung cancer during the treatments against EGFR as target).

Part 3 is entitled "simulation of the resistance to the targeted therapies by microfluidic" and aims to develop an approach concerning the analysis of single cells by a microfluidic approach using the resistance to EGFR-targeted treatments as a model. The next part of this project is to study the mutations of the circulating DNA of patients included in a PHRC-funded trial which will include 250 colon cancer patients at the time of recurrence, using the same technical approach.

Part 4 of the project aims to develop novel therapeutic approaches based on the developed CYP2B6TM-RED lentivirus on lung and ORL cancers (i/ analysis of its bystander and its immunomodulatory effects, ii/ inclusion of a miRNA-sequence into the vector to limit its biodistribution, iii/ test of other drugs that may be metabolized by CYP2B6TM and RED, iv/ combination with in vaccine-based therapeutic strategies to enhance the immunological response). This is a dynamic team headed by a solid and imaginative group leader with long standing track record on pharmacogenetics. This team have a very valuable know-how, appropriate national and international collaborations, including with several companies, and they have delivered constant high quality results in their field with a singular translational interest. An excellent exemple is their recent contribution by discovering the inefficiency of the anti-EGFR antibodies in patients carrying a mutation in the Kras in colon cancer by the fact that these results are used in national and international recommendations to select responsive patients.

The new project is in fact the continuity of the previous work, it is based on solid preliminary data, and they have interesting and original biobanks necessary for the project. Their projects have very clear translational as well as cognitive impacts in the fields of colon and lung cancer. Finally, they show a global move to clinically relevant questions that fit with the missions of INSERM.

Competences, expertises, techniques and facilities, including the sophisticated machines and tools necessary for the more recent microfluidic approach, required for the new projects are already largely mastered in the laboratory, or through ongoing and pertinent local and international collaborations. All the members of the visiting committee are convinced that all aspects of the project are realistic and feasible. The review took place on February 1 th 2013 at the present site of implantation of the Unit (UFR biomedicale des SAINTS-PERES). Oral presentations describing past and future research programs of the unit were made by the proposed director (Mr Pierre LAURENT-PUIG) and by the 5 project leaders participating in the new project. The visiting committee visited the Unit and also met separately (in the absence of the direction/team leaders), with the technical staff, researchers with permanent positions, non-permanent lab members (Students, Post-docs) and the representatives of institutional authorities (Paris Descartes University, UFR biomedical Saints-Peres and Inserm). All members of the committee were present from the beginning to the end of this visit and have participated to the final discussion on the report that took place at the end of the visit. They have also returned independently their argued comments to the chairman.

Grades

  spent at least 12 months in the unit* 3 Number of Research Supervisor Qualifications (HDR) taken 1 Qualified research supervisors (with an HDR) or similar positions 2  Assessment of the unit

  They organized the FFCD meeting from 2000 to present, the EORTIC on translational research in Paris in 2012, and organized or participated to the organisation of the European Science Foundation meeting in Spain in2007, 2008 and 2010.

Critères C1 Qualité scientifique et production C2 Rayonnement et attractivité académiques C3 Relations avec l'environnement social, économique et culturel C4 Organisation et vie de l'entité C5 Implication dans la formation par la recherche C6 Stratégie et projet à cinq ans

	A+	67	62	52	73	65	60
	A	57	67	71	45	65	63
	B	12	7	4	7	6	14
	C	0	0	0	3	0	1
	Non Noté	3	3	12	11	3	1
	Percentages
	Critères	C1 Qualité scientifique et production	C2 Rayonnement et attractivité académiques	C3 Relations avec l'environnement social, économique et culturel	C4 Organisation et vie de l'entité	C5 Implication dans la formation par la recherche	C6 Stratégie et projet à cinq ans
	A+	48%	45%	37%	53%	47%	43%
	A	41%	48%	51%	32%	47%	45%
	B	9%	5%	3%	5%	4%	10%
	C	0%	0%	0%	2%	0%	1%
	Non Noté	2%	2%	9%	8%	2%	1%
	Histogram

Grading

 Statistics by field: SVE on 10/06/2013

General observations 1/ Our team has always maintained an equilibrium between cancer and anticoagulants and immunosuppressor since they are both closely associated to hospital laboratory (leaded by two members of our team).

2/The number of HDR for 2014 is 7 and not 5 as reported. This number will increase to 9 before the end of the year.

3/ Since the writing of our project, the physicist intent to stay in our team and we are developing collaborations with physicists from the ESPCI, the Max Planck Institute and Paris Polytechniques school in order to reinforce this aspect of our project.

4/We have a strong interaction with medical and pharmacy school of Paris Descartes University allowing the recruitment of physicians in good agreement with our translational research orientation. Nevertheless we agree that we should increase the number of full time researchers to strengthen the basic research. In this regards, we identified, for the next four years, three potential scientist candidates who graduated their PhD in our team.


Paul Vidal

Grading

Once the visits for the 2012-2013 evaluation campaign had been completed, the chairpersons of the expert committees, who met per disciplinary group, proceeded to attribute a score to the research units in their group (and, when necessary, for these units' in-house teams). This score (A+, A, B, C) concerned each of the six criteria defined by the AERES. NN (not-scored) attached to a criteria indicate that this one was not applicable to the particular case of this research unit or this team. Criterion 1 -C1: Scientific outputs and quality; Criterion 2 -C2: Academic reputation and appeal; Criterion 3 -C3: Interactions with the social, economic and cultural environment; Criterion 4 -C4: Organisation and life of the institution (or of the team); Criterion 5 -C5: Involvement in training through research; Criterion 6 -C6: Strategy and five-year plan.

 Introduction History and geographical location of the unit:

A short introduction is required to understand the genesis of the Cognac project. At the departure of Mr Alain BERTHOZ to the College de France, in 1997, some of the members of his UMR remained at the Cordelier and created a new UMR. The first quadrennial period of the LNRS (Laboratoire de Neurobiologie des Réseaux Sensorimoteurs) was devoted to its organization. The unit started with five founding members and no engineers or technicians, on premises condemned by the Ministry, which necessitated to move to the Centre Medical des Saints Pères. The majority of the publications from this period were published in Experimental Brain Research. During the next two quadrennial contracts, the LNRS developed with great encouragement and support from the CNRS, the Paris Descartes University and the Ministry from these early days. It ended up with four teams and 40 staff members. In the years that followed, the unit went from publishing in Experimental Brain Research to the Journal of Neuroscience by way of the Journal of Neurophysiology. This trajectory was more or less similar to that of the other teams of the LNRS, with other journals depending on the field. The capacity to supply innovative projects had definitely improved.

In 2008, at the end of the third quadrennial contract of the LNRS, it was proposed two institutional solutions for the future. Firstly, the present group, with the addition of two teams, which wished to join, could be perpetuated under a new name, the CESEM (Sensorimotor Study Center). Secondly, the fusion of the neuroscience UMR on site could lead to the formation of a Neuroscience Institute. The second solution was preferred. The other UMRs did not approve the creation of the Institute and thus the current director is heading the newly founded CESeM for what is a fourth quadriennial contract. That led to 2012 with no major changes except that the former LNRS counted now six teams and 53 staff members. Because an Institute of Neuroscience could not be created with the other CNRS UMRs of the Centre Biomédical des Saints Pères, it was planned to create with IRBA (the military biomedical institute for the French ministry of Defense), ENS (Ecole Normale Supérieure) Cachan and Thales (Electronic systems company), a smaller structure call Cognac G (Cognition and Action Group, see project) with the perspective to create an UMR.

The Cognac G location will be shared beetween the Hôpital du Val de Grâce and the UFR Biomédicale des Saints Pères.

Management team: The « Cognac-G » project is original, innovative and multidisciplinary. Its main purpose aims at developing non invasive tools to quantify the behaviour of individuals, their biological, psychological and sociological characteristics and their genotypes. Therefore, by collecting such an amount of information, this project proposes to build databases in genomics, proteomics and ethomics to allow pertinent data mining, which is currently in a desesperate shortage. This unique approach will confer a strong political, economical and medical leverage to establish decision making in matters of social and health prediction and prevention.

In term of research teams, the entity « Cognac G » has four origins : (1) a part of the past unity directed by P.P. Vidal (CESEM, UMR CNRS 8194, Univ. Paris Descartes) (2) some groups of the SSA including the Neurological Department of the Val de Grâce Hospital (3) a core of mathematicians of the UMR CMLA (Centre de Mathématiques et de leurs Applications) at the ENS Cachan, (4) the team directed by a Head Engineer in Thales Training and Simulation.

To construct databases, the entity will use the follow-up of High Maintenance Cohorts (HMC) compound with soldiers, athletes and patients. However, these approaches in humans, mainly led in the sensory-motor field, will be paralleled by research in animal models. Therefore these databases will permit a consistent translational data mining oscillating from normal to pathological situations and vice-versa. This project includes real strengths. In humans, the proposal of combining appropriate sensors and actuators appears quite pertinent to define: decision processing, perceptivo-motor style and collaborative intelligence. Some teams of the past CESEM, in collaboration with Thales or Sport Authorities (FFR), are particularly experienced in these fields (sensori-motor transformation, vestibular function, flight simulation, robot to train the ruck…). Other members of CESEM have studied, in high level athletes, the human adaptation and its limits and how to avoid switching from an overreached (OR) situation to an overtraining syndrome (OTS). Finally, CESEM has conducted, in animal models, several studies on sensori-motor post-lesional plasticity: control of gaze and posture, skeletal geometry, scoliosis, trauma of the facial system, neuromuscular junction, all of them are relevant for the « Cognac G » project.

Alternatively, in animal models, the IRBA possesses a leadership position in the investigation concerning: chemical stress (dysfunctions of cholinesterases) and central nervous system irradiation. Besides IRBA plays a major role in the specification fields of aeronautics and military equipment (partnership with Thales, for instance with the Helmet Mounted Displays, HMPs). Moreover, one has to insist on the main contribution of the Neurological Department of the Val de Grâce Hospital concerning the taking care of patients suffering from brain irradiation sequelae.

Finally the CMLA of the ENS-Cachan has a strong expertise in the exploitation of the massive data flows generated. It will contribute to quantify human and animal behaviors and thereby to organize databases and datamining (preprocessing, exploration, reduction visualization, design of medical monitoring and diagnosis systems).

One may take into consideration that the entity « Cognac G » disposes of appropriate core and animal facilities (Université Paris Descartes and IRBA). Moreover, it benefits from the use of several major platforms (sensory-motor platform, flight simulators, sleep laboratory, night vision laboratory …) provided by Université Paris Descartes, IRBA, and Thales. Furthermore, Cognac G will collaborate with French military hospitals namely Val de Grâce Hospital through several departments (neurology, oncology, radiology, rehabilitation and intensive cares).

Weaknesses and threats:

There is some vagueness on how to address a number of critical issues concerning the necessary and sufficient parameters that capture the individual behavior. In the same vein, some operations which concern recording of cognitive and psychological parameters need to be better specified (number of subjects, type of questionnaires ….).

If multidisciplinary approaches are a real originality of this project they must not be sources of unwanted dispersion.

How research communities will handle data needs to be specified.

A calendar should be given on the temporal schedule of the different tasks. Some precisions are necessary concerning the definitive group composition and the concise appartenance of part-time researchers and technicians belonging to the different structures (CNRS, University, SSA, CMLA, Thales).

A particular attention has to be planned to keep confidentiality of participants data (chiefly SSA).

The inconvenience to use separate buildings will have to be surmounted.

Recommendations:

The originality of the project will have to emerge from the robustness of the future structure of this entity. Indeed, eventhough the management qualities of the current director are well known, he will have to deploy energy to install a strong synergy between physiologists, clinicians, mathematicians and engineers. A gap may exist between a written project and the reality of its daily application (using databases for data mining …). Moreover, the programs will take place in different sites, which is another putative difficulty. There is a necessity to reinforce certain fields with high level scientists such as human physiology and cognitive sciences to allow a concise identification of the critical physiological parameters.

Finally, one may insist on the shared enthusiasm of the participants and the strong support of the academic partners (CNRS, Université Paris Descartes, SSA) as well as that of the associated ones (ENS Cachan, Thales).

The committee is strongly supportive of the creation of the entity « Cognac G ». It will be one of the first to address the issue of the interindividual vulnerability and, thereby, should have an international impact.

3  Detailed assessments Assessment of scientific quality and outputs:

The aim of this new entity is multidisciplinary, translational and highly innovative and consists in building databases for datamining in normal and pathological situations.

Such an approach requires researchers originating from varied backgrounds (physiologists, clinicians, mathematicians, engineers) and their scientific quality and production are based on their past works and achievements. The analysis of the latter brings out that certain scientists, included in the project, are of high international level, alternatively others have been more widely involved in methodological and technological developments.

Taken together the different components of the entity indicate 142 publications since 2007 in international peer reviewed journals. Some of these journals are among the best of the speciality. One can cite articles in « The Lancet, Annals of Neurology, J. Neurosc., J. Neurophysiol., J. Neurochem., Neurobiology of Diseases, J. One can quote some pertinent researches led by the different participants. The CESEM has conducted quite extensive investigations in the field of the sensori-motor transformation. Thus, by studying three main types of information (visual, vestibular, somatosensory-proprioceptive) it has coined the concept of perceptivo-motor style. Such a concept, applied to athlete, patient, soldier will allow to predict how her/his motor system will react or express its plasticity in various contexts.

The CESEM, in collaboration with the IRBA, has developed some studies on the muscular junction and on the acetylcholinesterase (AchE) structure. Particularly, it has been searched how it was possible to act on the mechanism of inhibition by the organophosphorns compound (OPs).

Among the original works carried out by the IRBA it can be cited the studies on the mental fatigue and this on the perception of image similarities. Another quite innovative research is the sensor fusion and end-to-end latencies in projected images with the manufacture of helmet mounted displays (HMDs).

Finally, another major collaboration concerns Thales and the CESEM which have developed, for the first time in the world, a rugby scrum simulator.

Assessment of the unit's academic reputation and appeal:

The entity « Cognac G » is structured in one team with various competencies. If it is created; this will be the first unity of this nature in France and may be in Europe. Starting with about 22-24 fulltime or part time searchers or technicians (CNRS, University, SSA, ENS-Cachan, Thales, INSEP (Institut National du Sport, de l'Expertise et de la Performance), this innovative project should be attractive for senior investigators and postdoctoral or doctoral students. The appeal, existing already via the reputation of the CESEM and several groups of the SSA, may interest; physiologists of sensory-motor control, cognitive neuroscientists of motor planning, clinical neuroscientists, mathematicians, engineers, sport researchers, toxicologists. The entity will be financially supported by the annual and recurrent funding of the academic partners (CNRS, University, SSA) but it will be necessary to get successful applications from other funding institutions (ANR, European Community, foundations …).

Assessment of the unit's interaction with the social, economic and cultural environment:

Different components of the entity have established, in the past, interactions in several fields.

At the economic and social levels, the CESEM has developed strong collaboration with Thales. In a first step, it was to use flight and driving simulators. Then, the CESEM and Thales imagined and realized a rugby scrum simulator. This simulator meets critical requirements to reduce accidents and also is a tool for coaching purposes and match preparation. One sees that is was a joint approach between research, industry and sport authorities (FFR, Fédération Française de Rugby).

Another research, with a social and cultural impact, concerns the overreaching (OR) detection in endurance trained athletes. The CESEM has analyzed this state (OR) in order to avoid that it switches toward an overtraining syndrome (OTS) which represents a threat for both athletic performances and health.

The IRBA plays a major role in the specification field of aeronautics and military equipment in partnership with industrial firms (Thales ...). Moreover, the IRBA via two of these departments, is widely involved in the relevance of the human factors (environnemental constraints, overexposure, interactions with complex systems …).

The IRBA may furnish some lines of progress in telemedicine via the programs it developed for the armed forces. Another contribution can be brought by the neurological department of the Val de Grâce Hospital in matter of taking care the patients suffering from brain irradiation sequelae.

Assessment of the unit's organisation and life:

Eventhough this item is not applicable, it appears essential to insist on the necessity for the future director to set a robust synergy between the different searchers and their different thematics. It is clearly indicated in the chapter « organigramme fonctionnel et règlement intérieur », this will have to be respected to avoid dispersion and inefficacy.

Assessment of the unit's involvement in training through research:

Assessment of the five-year plan and strategy:

The strategy over the next five years includes two main ensembles (in humans and animal models) of particular projects which are globally in continuity with previous know-how and results displayed by the CESEM, the IRBA and Thales.

Sensors and actuators (and their combinations) are presently available. The major challenge will be to synchronize them to collect the data and to construct the databases for subsequent datamining. At this level, the role of the mathematicians of the CMLA will be crucial for: pre-processing, reduction and exploitation of the massive data flows.

Either in humans or in animal models data computing will deal with three major thematics: Health, Sport, and Defence.

In humans, the data will be collected from the High Maintenance Cohorts (HMC) composed with patients athletes and soldiers by the use of pervasive or ubiquitous computing.

Three main axes will be developed: (1) Decision processing and context dependent adaptation. The analysis, conducted in flying simulators, will try to unravel which cues are crucial and how they combine to evoke fast motor decisions and/or context specific adaptation (responses to fall or to sudden acceleration …); (2) The perceptivo-motor style has been particularly studied by the CESEM. This approach, « the smart check project » should allow to define how different group develop proper strategies based or "weighing or reweighing" one or another of information (visual, vestibular, proprioceptive). This can be applied to patients: seniors at risk of fall, traumatic brain injured or stroke suffering patients or also to high level rugby players … (3) Collaborative intelligence, this subproject concerns the use of sensors and actuators to quantify the anonymity of collective intelligence and motor planning. Two studies will be led: (a) a first on the trainer-trainee duo in flight simulators with a particular attention to autonomous and emotional responses during flight maneuvers; (b) another one using the robot to train the ruck in rugby. In this approach the collaborative sensorimotor behavior will be investigated.

In animal models, the studies will be centered to the post-lesional plasticity of the central and peripheral nervous systems. They will be a natural follow-up of HMC. They concern three axes widely developed by the CESEM and the SSA, they are classified according to three kinds of stress. (1). Chemical stress, function and dysfunctions of cholinesterases (AchE). This research consists to understand the mechanism of the toxicity of the organophosphates (OPs) and to strive to cure or to reduce their deleterious effects. A possible key to this issue can be provided by genetic analysis including mouse strains in which the putative targets (AchE and butyrylcholinesterase) are removed in a tissue specific manner. Such a "toxigenomic approach" appears relevant in a field where no curative therapeutic exists; (2) Mechanical stress: repair following facial nerve section. This subproject is really original. Using different types of lesion experiments, it is, in particular, proposed to study the role of certain molecules (ephrins and their receptors) in axonal guidance or of the lithium which stimulates the expression of myelin genes. (3) Brain irradiation, neuroprotectives agents. The SSA possesses a real leadership in this field with a strong potential of translational research in humans with patients suffering from brain irradiation. In this specific subproject it will be emphasized on the neuroinflammation induced by radiation and more precisely on the changes which occur at the level of the bloodbrain-barrier (BBB). It will be screened neuroprotective agents dedicated to pericyte-endothelial cell normalization.

In total, the global project is coherent and partly relies upon solid scientific works previously carried out by the CESEM, the SSA and Thales. Its ultimate purpose is excellent and very innovative. The program is original, ambitious and multidisciplinary. This cooperative program responds to a strong need of building multimodal data banks in order to allow pertinent datamining. The latter stagnates in a desesperate shortage or is weakly developed. The proposed database will be constructed via the follow-up of High Maintenance Cohorts (HMC) using soldiers, athletes and patients. This will permit to establish, in parallel to translational research using animal models, solid foundations for a real predictive and preventive medicine.

Histogram

The members of the Cognac G project would like to thank the member of the visiting panel and its President for their encouragements and constructive remarks.

Major points

"There is some vagueness on how to address a number of critical issues concerning the necessary and sufficient parameters that capture the individual behavior."

The group has the necessary competences to address some issues concerning neurophysiology, ergonomics, clinics, engineering and mathematics necessary to record, databases and data mining individual behavior. It was unable to attract a skilled psychologist and ethologist, which is not surprising given the main orientations of Cognac G, which are more centered on the quantification of the physiological aspects of individual behavior. We have therefore asked two colleagues to advise us on these matters for the coming years, Martin Giurfa and Florian Waszak (who is next door). They have kindly accepted this task. This point was a real preoccupation during the genesis of the project but was insufficiently taken into account during the redaction of the project and at the time of the visit.

"If multidisciplinary approaches are a real originality of this project they must not be sources of unwanted dispersion."

That is a real danger for the project. The way we intend to deal with that problem is to focus on very precise projects with stringent timetables. We also intend to create for each project a steering committee including not only the colleagues involved in the project but also external consultants (see above), which will meet to establish progress reports and recommendations. We are reasonably confident that it can be done because the group, at least for some part of it, has already worked on multidisciplinary projects in the last three years and ended up with a final product and/or a publication in due time. An emblematic example for us was the ruck simulator.

How research communities will handle data needs to be specified" Data definitely are the pivotal factor within the Cognac G initiative. For their collection, management and monitoring, several formal aspects need to be sorted out such as security, confidentiality, intellectual property. On these aspects, we will follow the recommendations from the relevant authorities (Institut Droit et Santé, CNIL, SGDSN, DCRI,) in order to comply with the legal framework. The data and their various representations (summaries, indicators, visual displays) will form the central vector of communication between the different communities. We aim to develop a secured collaborative framework connecting the databases through a web platform, which will render them accessible in a remote mode from the members of the team. The platform will make possible to upload/download data and metadata, aggregate data, operate statistical operations, and obtain visual displays, share data and observations. In order to design and implement this framework, we will rely on two things: (a) the experience of the Image Processing Online (IPOL <http://www.ipol.im>) initiative at CMLA/ENS Cachan which already offers similar services, (b) the first pilot projects within Cognac G will provide as an outcome procedures and specifications for the data handling part in the long run. Therefore the introduction of protocols, standards and formats for the data to be collected will be conducted through the interaction of data scientists and engineers with neurophysiologists and neurologists.

A particular attention has to be planned to keep confidentiality of participants data (chiefly IRBA).

This is indeed a challenge. Practically speaking we intend to compartmentalize the functioning of Cognac G at several levels. In term of collaboration we will have no cooperation with sensitive countries concerning the theme "Smart simulator " and Smart Flat". In addition, no citizens form sensitive countries will be authorized to work at the Val de grace and at these locations without specific authorization. Also, since the ARES panel visited us, I had extensive discussion with Mr. Nowak from the DCRI and Mr. Gasnot, in charge of the questions concerning defense at the CNRS to define a politic for the new UMR. Finally, a vice-director issued from the Service de Santé des Armées will be chosen by the SSA and he/she will be in charge of the questions concerning security.

"The inconvenience to use separate buildings will have to be surmounted."

It is for sure a problem we will have to overcome but there was simply no way to install the researchers working o animal research on the Val de grace location, both in term of facilities and space. That' said, the two locations are as close as some facilities on many large American campus and we have easy to use public transportation and parking places available at the two locations.

"A calendar should be given on the temporal schedule of the different tasks". Xavier

Please see the table below for some of the project in human, which are the more prone to roadblocks. The studies in animal models pose fewer problems in term of methodologies And therefore should progress more smoothly. "Some precisions are necessary concerning the definitive group composition and the concise appartenance of part-time researchers and technicians belonging to the different structures This composition may not be definitive since some colleagues have asked to join the group.

  Physiol. (London), Exp. Br. Res., Neurooncol., Toxicology, Endocrinology, Current Opin. Oncol., Machine Learning Journal, Trans. Biomed. Eng., Theory, J. of Mathematical Imaging and Vision, Vision …. ». Nine patents were filled during the last 4 years by certain components of the entity (cellular imaging, detection and prognosis of Parkinson disease, recognition of objects and shapes, video demultiplexing based on meaningful mode of extraction).

  P.P. Vidal created a specialty on Neuroingineering in the Biomedial Engineering Master Program of Paristec-Paris Descates. Besides, he organized, for a year, a panel for the Ministère de la Défense on Man Machine Interface. A proposition to create a Master in Biomedical Engineering exists with chinese Universities (Shanghai, Dentzi).

  Hôpital d'Instruction des Armées du Val-de-Grâce Address: 74 boulevard de Port-Royal, 75005 Paris Conduct or programme of visit: 8h30 -9h00 Huis clos -Présentation de l'AERES au comité par le Délégué 9h00 -9h15 Devant l'unité, présentation du Comité de visite et Présentation de l'AERES par le Délégué 9h15-10h Présentation de l'unité, bilan et projet par M. Pierre Paul VIDAL. AUDITION DES EQUIPES 10h00-10h20 Quantifying natural movements in behaving humans (S. COUVET) 10h20-10h40 Building databases and using decisional algorithms to study phenotypes (N. VAYATIS) 10h-40-11h00 CNS lesions following brain irradiation, how to check patients with severe cognitive and motor dysfunction? (D. RICARD) 11h00-11h15 Pause 11h15-11h35 CNS post lesional plasticity of the vestibular and facial system (C.DE WAELE) 11h35-11h55 CNS post lesional plasticity: the cholinergic system (E. KRECJI) 11h55-12h15 CNS post lesional plasticity, toward a stratified rehabilitation (A. YELNIK) 12h15-12h30 Sensorimotor adaptation to man-machine interface (S. BUFFAT) 12h30-14h Déjeuner SESSION RENCONTRE AVEC LE PERSONNEL PERMANENT ET NON PERMANENT Le comité se répartit en trois sous-groupes 14h -14h45 Rencontre avec les ITA titulaires, CDD Auditoire : membres du Comité, représentant ITA, Délégué AERES, sans la Direction Rencontre avec les doctorants et post-doctorants et/ou CDD « chercheurs », Ingénieurs Auditoire : membres du Comité, Délégué AERES, sans la Direction Rencontre avec les chercheurs et enseignants chercheurs titulaires Auditoire : membres du Comité, Délégué AERES, sans la Direction 14h45-15h Pause 15h-15h45 Rencontre avec les représentants de la Tutelle: Auditoire : membres du Comité, Délégué AERES 15h45-16h15 Rencontre avec la direction de l'unité Auditoire : membres du Comité, Délégué AERES 16h30-18h30 Réunion du comité à huis clos Présence : membres du Comité, délégué AERES 5  Statistics by field: SVE on 10/06/2013

Unit workforce Number as at 30/06/2012 Number as at 01/01/2014

	M. Pierre-Paul VIDAL AERES nomenclature: SVE1_LS4 Physiology, physiopathology, medical systems biology, SVE1_LS5 Neurobiology Unit workforce: N1: Permanent professors and similar positions N2: Permanent researchers from Institutions and similar positions N3: Other permanent staff (without research duties) N4: Other professors (Emeritus Professor, on-contract Professor, etc.) N5: Other researchers from Institutions (Emeritus Research Director, Postdoctoral students, visitors, etc.) N6: Other contractual staff (without research duties) TOTAL N1 to N6 Percentage of producers Unit workforce Number as at 100 % 6 8 7 0 3 24 30/06/2012 Number as at 2014-2018 Number of project producers 6 8 7 3 24 01/01/2014 Doctoral students Theses defended Postdoctoral students having spent at least 12 months in the unit* Number of Research Supervisor Qualifications (HDR) taken Qualified research supervisors (with an HDR) or similar positions 2

 Assessment of the unit Strengths and opportunities:

Grades Critères C1 Qualité scientifique et production C2 Rayonnement et attractivité académiques C3 Relations avec l'environnement social, économique et culturel C4 Organisation et vie de l'entité C5 Implication dans la formation par la recherche C6 Stratégie et projet à cinq ans

	A+	67	62	52	73	65	60
	A	57	67	71	45	65	63
	B	12	7	4	7	6	14
	C	0	0	0	3	0	1
	Non Noté	3	3	12	11	3	1
	Percentages
	Critères	C1 Qualité scientifique et production	C2 Rayonnement et attractivité académiques	C3 Relations avec l'environnement social, économique et culturel	C4 Organisation et vie de l'entité	C5 Implication dans la formation par la recherche	C6 Stratégie et projet à cinq ans
	A+	48%	45%	37%	53%	47%	43%
	A	41%	48%	51%	32%	47%	45%
	B	9%	5%	3%	5%	4%	10%
	C	0%	0%	0%	2%	0%	1%
	Non Noté	2%	2%	9%	8%	2%	1%

 Supervising bodies' general comments


Grading

Once the visits for the 2012-2013 evaluation campaign had been completed, the chairpersons of the expert committees, who met per disciplinary group, proceeded to attribute a score to the research units in their group (and, when necessary, for these units' in-house teams). This score (A+, A, B, C) concerned each of the six criteria defined by the AERES. NN (not-scored) attached to a criteria indicate that this one was not applicable to the particular case of this research unit or this team. Criterion 1 -C1 : Scientific outputs and quality ; Criterion 2 -C2 : Academic reputation and appeal ; Criterion 3 -C3 : Interactions with the social, economic and cultural environment ; Criterion 4 -C4 : Organisation and life of the institution (or of the team) ; Criterion 5 -C5 : Involvement in training through research ; Criterion 6 -C6 : Strategy and five-year plan.

The unit was originally created in 2005 under the direction of Mr Marco GIOVANINI. Mr Marco GIOVANINI left for a position in Los Angeles and gave the direction over to Ms Jessica ZUCMAN-ROSSI (JZR). The Unit was renewed in 2009 under her direction and will remain as such in the project for 2014-2019.

The unit is located on the premises of the Institut de Génétique Moléculaire of the University Paris 7, in the same building as the CEPH (centre d'étude du polymorphisme humain), in close vicinity of the Institut Universitaire d'Hématologie. For the next 5 year period, the unit will be joined by a team coming from UMR_S940, which is located one floor above within IGM. At the same time two groups are leaving the unit to respectively join the Pitié-Salpétrière and the HEGP (Hôpital Européen George Pompidou) to develop their work.

Hence the new project will be refocused on liver carcinogenesis (Hepatocellular Carcinoma [HCC] and adenoma), Mesothelioma and studies related to the roles of mRNA translation in the regulation of the p53 pathway and immune evasion.

Management team

The present unit is single team lab structured in 4 thematic projects. It is a rather small structure with a director assisted by a single administrative staff. No management structure is described. 2  Assessment of the unit

AERES nomenclature

Strengths and opportunities

Two strong teams developing excellent science.

International recognition and strong ties abroad.

Strong ties of the team leader with the Sanger Centre.

The team leader has over the past 5 years managed to be a central actor in the hepatocellular cancer field, in somatic genetics and more recently in predisposition and risk factors governing progression from benign to malignant disease.

Exceptional ties with the clinics in the field of liver cancer. The prospect of the team in Jean Verdier Hospital in Bondy joining the lab is considered a great opportunity. However, it may also be a threat (see below).

Unique positioning on mesothelioma. Only few teams have this expertise and such a collection of samples from a devastating disease, whose incidence may be rising due to other micro and nano fiber pollutants besides asbestos.

Recognized expertise of the new PI joining the lab in the p53 and immune evasion fields.

Strong support by Inserm in terms of yearly funding (high) and technical staff.

Weaknesses and threats

The scientific environment was felt as lacking dynamism and the lab to be working on its own. The management plan needs to be clarified.

Interactions between both groups could be tightened.

Association with the clinical team in Jean Verdier Hospital in Bondy is both an assett and a threat. Since they are fairly distant from the site, keeping active ties will require determined action in the long run. Moreover, the team in Bondy is diverse (radiology, pathology, hepatology) and very clinically oriented, while the basic research team is centered on genomics and genetic aspects.

Integration and interactions with the Jean Dausset Foundation and neighboring labs and core facilities might be developed.

Bioinformatics development is good but still not sufficient given the importance of bioinformatics in many projects of the unit.

Recommendations

Set up a management team.

Develop internal scientific life and interactions between both teams. improve relation with the Jean Dausset Foundation to improve integration of the Unit on the site. Everyone would benefit from it.

Ties with the neighboring IUH should be formalized.

Implement a pro-active strategy to attract new groups.

 Detailed assessments Assessment of scientific quality and outputs

The unit has clearly excellent scientific outputs, with 127 publications in peer reviewed journals published by the unit in its present constitution. This number goes up to 182 including publications by the newcoming group. In total both teams have published 33 papers in journals with IF exceeding 10 (Nature, Nature genet, Cancer Cell, Mol Cell, Blood, JAMA, PNAS…).

Assessment of the unit's academic reputation and appeal

The present reputation of the Unit is directly related to that of her director, whose work in the field of tumor genomics is well known and respected at both the national and international level. The addition of the new Team will further incresase the Unit's reputation and scientific quality. Indeed, the new team leader has contributed high profile papers to the very active field of p53 regulation. He made original observations that have brought clear novelty.

Both teams have hosted (and are hosting) a number of doctoral and post-doctoral students from abroad. This clearly indicates their strong reputation and appeal.

Assessment of the unit's interaction with the social, economic and cultural environment

The unit has filed and licenced a patent with Integragen SA and has plans on developing collaborations with this company. Results on Hepato Cellular cancer and Adenoma molecular subtypes are expected to have a strong impact on patient management and care in the future. The foreseen integration in the Unit of the group at the Jean Verdier Hospital is expected to increase the social impact. However, attractivity towards young PIs could and should be improved.

Assessment of the unit's organisation and life

The unit is presently a rather small structure which seems to run on an informal setting. No clear mention is made in the written report of regular lab meetings, however, the addition of a new research group and that of the team of clinical researchers at the Hospital Jean Verdier in Bondy should make it necessary to define a formal structure of governance and formalize regular staff meetings and annual retreats.

Assessment of the unit's involvement in training through research

The number of PhD students (4 PhD students; 87 months) in the last 5 years is very good, although some improvement is possible. Students are given appropriate conditions to successfully reach their objective in 3 to 4 years and are encouraged to find post-doctoral positions abroad (in Europe or the US). They are provided with adequate assistance and supervision from their tutors and often can obtain also assistance by other students in the same group or from another group. Teamwork is well integrated in the lab culture. Possibilities of presenting their work are given during formal labmeetings, and during national or international congresses or seminars. Students also underscored that they have the possibility of interacting with their mentors in a rapid and informal fashion when required. Authorship on papers is not a source of dispute.

Assessment of the five-year plan and strategy

The strategy of the unit is clearly defined and focused on cancer genomics for what concerns team 1 and regulation of mRNA translation for Team 2. However, whereas the scientific plans of the respective teams appear clearly, future interactions and synergies between both teams have not been developed and it is felt that the unit would clearly gain from some reflexion at this level. Some hints could be given on p53 response to Endoreticulum stress and oxidative stress and some of the mutated genes acting in this pathway identified in the exome screens in HCC.

Moreover, the second objective presented by Team 2 on sporadic cancer in dogs in a comparative oncology program at the European level needs further clarification. Asked to clarify this point, the team leader explained that he is part of a group that has filed a COST action proposal that was not selected this year but ranked in good position, encouraging the promoters to resubmit in the future. Hence, how this program on canine cancer will impact on future projects in the Unit is not clear. The unit has clearly excellent scientific outputs, with 127 publications in peer-reviewed journals published by the unit in its present constitution. Among this abundant production, the number of articles in high impact journals is of particular note (Nature 2009, Nature Genetics in 2012, J Exp Med, Hepatology as senior authors).

-

The team has singled out three themes/projects that will be continued in the next term: (1) molecular profiling and functional genomics of HCC and hepatic adenoma, (2) genetic predisposition in HCC, (3) molecular profiling of mesothelioma.

(1) molecular profiling and functional genomics of HCC and hepatic adenoma is under the direct supervision of the Unit's director. It is the area of research where the unit has in the current setting made the most outstanding production and on which it built its reputation. Outstanding observations such as the characterization of IL6/ STAT3 activation in cellular models overexpressing the different gp130, STAT3 and GNAS mutants identified in hepatocellular carcinoma (Nature 2009, J Exp Med 2009) are noticeable. Along the same lines the recent NGS screen of HCC which led to the identification of important oncogenic targets (WNT/ -catenin, IRF2, RSK2, ARID…. Nature Genetics, 2012). Each of these projects is built on unique and innovative approaches beyond the state-of-the-art. Furthermore, the team is remarkable for its excellent translational research such as the identification of distinct molecular subtypes of HCC (Hepatology 2007). In each of these different studies, the Laboratory has published in high impact journals.

(2) genetic predisposition in HCC. This project benefits from the expertise in the Unit in the identification of novel therapeutic targets and detailed knowledge on molecular pathways involved in HCC development. The interdisciplinary network the investigators have set up must be emphasized. The focus of the project is directed to a better understanding of early events in hepatocarcinogenesis with the aim of identifying patients who are at particular high risk of HCC. The whole project is based on genome wide association and involve GWAS studies, functional study of identified SNPs (when relevant), validation of the SNPs showing association in cirrhotic patients. This is a highly relevant project led by recognized experts in the field. Incidence of HCC is expected to increase in the next years and only a few effective therapeutic approaches exist. The group has built a large interdisciplinary network in France and abroad.

(3) molecular profiling of mesothelioma is led by a young CR1 INSERM, who joined the group 3 years ago and is associated to a researcher who historically started the work and is well introduced in sub-specialty networks. Globally, this theme is underrepresented in Team n°1, compared to the HCC theme. The project is based on molecular profiling and genomic approaches classically used in Team n°1 (transcriptome and sequencing, genome wide methylation profiling and miRNA expression patterns). There is a clear wish to develop functional approaches, using mesothelioma cell cultures the group has developed, and tumor samples. It is of note, that tumor samples are rare (it is not a frequent disease luckily) but the group has the proper networks in the field. The group is also interested in translational approaches and foresees different strategies to screen chemical compounds that could potentially inhibit carcinogenesis in subgroups of mesothelioma tumors. The level of publication is not comparable to that of the group working on hepatocellular tumors but the group is smaller and all the work currently being performed has not yet been published. Notably, the two permanent researchers of the group have jointly signed (first and last coauthors) the two most recent publications in specialty journals (Arch Pathol Lab Med, Am J Pathol.).

Assessment of the academic reputation and appeal

-

The Laboratory is renowned for its expertise in deciphering the molecular genetic basis of HCC.

-The numerous invited reviews, commentaries and opinion articles (Hepatology, J Hepatology, J Clin Oncol, Dig. Surg., Digestive and Liver Disease, etc) witness the high international academic reputation of this laboratory.

-

The team leader sits on a number of scientific panels in France (INCa, LIGUE, Fondation de France, INSERM…) and abroad (AICR, WELBIO, Cancer Research UK, and many others) indicating the high level of recognition.

-

The team is "équipe labelisée de la Ligue contre le Cancer, is a major partner in the ICGC program on HCC.

-The team leader is frequently invited to talk in plenary lectures in French (n=25) and international congresses (n=64) and has been awarded the Prix de la Recherche 2012 de l'INSERM. Those are clear signs of her high level of recognition in the academic world in France and at the international level.

Assessment of the interaction with the social, economic and cultural environment -

The written report makes mention of one patent that has been licensed to INTEGRAGEN SA in 2011 and one other patent in the process.

-Few collaborations with industry are mentioned.

-It must be acknowledged that improved diagnosis or molecular sub-classification of HCC will indirectly benefit HCC patients and their families and should have an important social impact (in the long-term). The excellent publication record should facilitate securing funding, including from international agencies.

Assessment of the unit's organisation and life

-International visibility, the proven track record and the fact that the proposed projects continue to build on existing biobanks future prospects of collaboration with the group at the jean Verdier Hospital in Bondy datasets are clear strengths of this group.

-

The genetic predisposition project is considered a hot topic and an excellent opportunity to further increase the scientific impact of the findings that have been generated so far in the team. The group has the necessary know how to reach the objectives of the project and can rely on an established network of investigators and a large number of biological samples, patients and clinical data A unique collection of primary cultures of 70 MPM (malignant pleural mesothelioma) samples established in the laboratory and characterized at the genetic and transcriptomic levels and good collaboratiions (HEGP, French Mesobank network) securing access to mesothelioma tumor collections Strong support from the "Carte d'Identité des tumeurs" program from the LNCC  Weaknesses and threats -

The Laboratory is planning to embark on a number of challenging projects, including some genomic, transcriptomic and methylomic large-scale projects. Although the group is well connected within the genomic community (numerous collaborations with leaders in the field, these heavy duty genomics projects involve a number of important challenges. These include the acquisition or privileged access to high-throughput sequencers (HiSeq or long-read sequencer) and a state-of-the -art computing infrastructure (data storage, computing power), as well as extensive bio-computing capacity Only one definition of cirrhosis is given as a "control" group. However, there are several grades of cirrhosis according to measurements or criteria such as elastography, hepatic venous portal gradient, Child-Pugh score, and so on. These sub-categories of cirrhosis, together with the different etiologies should be considered.

-Also non-cirrhotic liver tissue should be included in these studies. Recent epidemiological studies indicate that in non-alcoholic steatohepatitis the risk of HCC may be significantly increased already before the development of cirrhosis.

The small size of the mesothelioma group and the variety of its projects may be a threat to their production and visibility in a a highly competitive field. Hiring additional students and post-docs should be considered rapidly to strengthen this interesting line of research with important public health implications.

 Recommendations

At the moment, it seems that the Laboratory is capitalizing on outstanding collaborations, but they might consider investing also in staff members with the appropriate expertise to avoid being dependent on external collaborators.

-Future projects will need functional validation using molecular and cellular biology. This seems an important aspect of research to invest in and prioritize. So far, the combination of genetic (sequencing) and functional (molecular biology) expertise has been one of the unique strengths of the Laboratory.

-Mesothelioma

The current funding of this subgroup of team n°1 is not clear but it would be necessary to extend it by recruiting at least a post-doc and a PhD student.

The health risk that pose carbon nanotubes is very concerning if confirmed. The expertise of the group could probably be better used to address this important question.

Detailed assessments

Assessment of scientific quality and outputs Scientific production is of very high quality relative to the size of the research group with regular publications in journals with high impact factor (in average, one publication / year in journals with IF > 10). These publications are related to the 2 main basic research themes of the group that aims at understanding the importance of mRNA processing in regulation of the p53 tumor suppressor pathway and in immune evasion during viral infection. In addition to these major publications, members of the group have been participating in collaborative projects that led to several good to excellent publications. Basic research programs are well supported by important funding ressources from INSERM and national agencies (ANR, INCa, ARC).

Regarding the 2 more translational research projects, the team leader announces that he has been coordinating a european network aiming at using the dog as a pre-clinical model for cancer research. This informal network has filed a COST action proposal that was not selected but got a reasonable rank, inciting them to renew the proposal. It is, however, difficult to evaluate its impact on the projects developed by this team. Scientific aims were not clearly defined and COST actions fund meetings where actors in a given field exchange information.

The team leader is also the scientific head of a medium-throughput screening facility dedicated to proteinprotein interaction modulators that fosters collaborative projects with regular publications. No patent from this activity is yet available. This activity led the team leader to organize an EMBO workshop in 2012.

Assessment of the unit's academic reputation and appeal

The scientific production has provided the group with an excellent reputation, in particular in the p53 field which has been its most productive line of research. This scientific production led to the re-evaluation of some dogmas in the p53 field and has unraveled very interesting regulatory mechanisms that might play important roles during aging and carcinogenesis. Their findings regarding immune evasion during viral infection is also important and might lead to novel original therapeutic approaches in the future. The research group is well connected and is driving interesting collaborations, at both the national and international levels. The group is attractive for students and postdocs. Lack of information on their participation as invited or selected speakers in international meetings does not allow full evaluation of their academic influence.

Assessment of the unit's interaction with the social, economic and cultural environment

The team leader is the scientific director of the protein-protein interaction facility that aims at identifying small compounds with potential therapeutic applications. Again, little information was provided to the reviewers to assess the importance of the facility but it appears to be involved in collaborative projects with regular publications. The network on dog-oriented research is at its early stage so it is difficult to predict its added value.

Assessment of the unit's organisation and life

The team's life is centralized on its PI, who is the only senior researcher present on a day to day basis in the lab. The team leader expressed his deep satisfaction to join forces with Team n°1 and develop scientific interactions with this team.

Assessment of the unit's involvement in training through research

The team hosted numerous students at both the master and PhD levels. All PhD students have been very successfull and ended their program with at least one publication as first authors in high impact factor journal. This is likely to reflect an excellent mentorship and scientific environment. One PhD student set up on her own initiative a meeting related to the p53 field that was restricted to PhD students. The group also hosted several junior and senior post-docs, including foreign post-docs. One senior post-doc will leave the RF lab soon to start his own "Avenir-ATIP" junior group.

Assessment of the five-year plan and strategy

Human ressources dedicated to the 4 main research programs (2 basic and 2 translational) were not sufficiently described in the written report but this point was clarified during the visit. The p53-related projects are developed by sufficient number of students and post-docs. However, due to the departure of one senior post-doc that was key to projects related to immune evasion, it will be important to re-inforce human ressources dedicated to this program to maintain competitivity at the international level.

Conclusion

 Strengths and opportunities

The group develops excellent basic research programs with potential applications in oncology and immunity. Translational programs are of potential interest, with interesting perspectives in developing original therapeutic strategies, but yet not completely mature.

 Weaknesses and threats

The translational dog-orientated research program is both promising and challenging. However, it is not clear how the group will integrate this project with the ongoing basic research programs and with the rest of the unit research lines, including those that are currently developed by team 1. In particular questions arise on time constraints that may arise due to time consuming networking activities; that may contradict the need to maintain leadership on his fundamental aspects. Given the fact that the team leader is the only permanent staff scientist in his team, this may be a major threat.

 Recommendations

Hiring permanent staff scientists at the "chargé de Recherche" level could help re-inforce the leadership of the group within its scientific community, and help the group leader supervize a research group that will likely increase in size in the coming years. Improvements in the management strategy and organization of the unit should be discussed with the head of team 1 to provide a more attractive environment for young PIs.

 Conduct of the visit

  spent at least 12 months in the unit 4 Number of Research Supervisor Qualifications (HDR) taken 1 Qualified research supervisors (with an HDR) or similar positions 7 10  Detailed assessments Assessment of scientific quality and outputs -

  See assessment of the unit Assessment of the team's involvement in training through research See assessment of the unit Assessment of the five-year plan and strategy See identical assessment of the unit Conclusion  Strengths and opportunities -

  Other professors (PREM, ECC, etc.) N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitors

Unit workforce Number as at 30/06/2012 Number as at 01/01/2014

	SVE1_LS1; SVE1_LS2; SVE1_LS7 Unit workforce Unit workforce N1: Permanent professors and similar positions N2: Permanent researchers from Institutions and similar positions N3: Other permanent staff (without research duties) N4: Other professors (Emeritus Professor, on-contract Professor, etc.) N5: Other researchers from Institutions (Emeritus Research Director, Postdoctoral students, visitors, etc.) N6: Other contractual staff (without research duties) TOTAL N1 to N6 Theses defended Postdoctoral students having spent at least 12 months in the unit* Number of Research Supervisor Qualifications (HDR) taken Percentage of producers Doctoral students Qualified research supervisors (with an HDR) or similar positions	Number as at 30/06/2012 5 4 6 1 8 24	15 9 10 1 9	Number as at 01/01/2014 8 3 6 1 10 28	2014-2018 Number of project producers 8 3 6 1 6 24

2013 Grades Critères C1 Qualité scientifique et production C2 Rayonnement et attractivité académiques C3 Relations avec l'environnement social, économique et culturel C4 Organisation et vie de l'entité C5 Implication dans la formation par la recherche C6 Stratégie et projet à cinq ans

  Programme du Comité de visite Unité Génomique fonctionnelle des tumeurs solides 17 01 2013, 27 rue Juliette Dodu, 75010 Paris Directeur actuel : Ms Jessica ZUCMAN-ROSSI Directeur proposé : Ms Jessica ZUCMAN-ROSSI Auditoire : membres du Comité, Délégué AERES, sans les Tutelles, ni la Direction Rencontre avec les doctorants et post-doctorants et/ou CDD « chercheurs », Ingénieurs Auditoire : membres du Comité, Délégué AERES, sans les Tutelles, ni la Direction Rencontre avec les chercheurs et enseignants chercheurs titulaires.

	Délégué scientifique AERES: Daniel Olive A+ 67 62	52	73	65		60
	Comité Scientifique : Mr Charles THEILLET (Président) ; Experts Mr Diether LAMBRECHTS, Mr Andrea DE GOTTARDI, Mr Laurent LE CAM, Ms Marie-Paule ROTH (CSS2), Mr Philippe MARTEAU (CNU) A 57 67 71 45 65	63
	8h30 -9h00 B	12	Huis clos -Présentation de l'AERES au comité par le Délégué 7 4 7	6		14
	9h00 -9h15 C	0	Devant l'unité, présentation du Comité de visite et Présentation de l'AERES par le Délégué 0 0 3 0	1
	9:15-9:45 Non Noté	3	Ms Jessica ZUCMAN-ROSSI: Présentation de l'unité, bilan et projet 3 12 11	3		1
	9:45-10:00		Discussion
	Percentages AUDITION DES EQUIPES 10:00-10:10 Ms Jessica ZUCMAN-ROSSI: Introduction of team 1 projects 10:10-10:20 Ms Camilla PILATI: Genomics of hepatocellular adenoma 10:20-10:30 Ms Sandra REBOUISSOU: Functional analysis of new therapeutic targets Critères C1 Qualité scientifique et production C2 Rayonnement et attractivité académiques C3 Relations avec l'environnement social, économique et culturel C4 Organisation et vie de l'entité dans la formation C5 Implication par la recherche	C6 Stratégie et projet à cinq ans
	10:30-10:40 10:40-11:15 A+	48%	Mr Pierre NAHON: Genetic predisposition to liver tumors Discussion 45% 37% 53%	47%		43%
	11:15-11:30 11:30-11:45 A	41%	Coffee break Mr Didier JEAN: Mesothelioma projects 48% 51%	32%	47%		45%
	11:45-12:00 12:00-12:30 B	9%	Discussion Mr Robin FAHRAEUS: Team 2 projects 5% 3%	5%	4%		10%
	12:30-13:00 C	0%	Discussion	0%	0%	2%	0%		1%
	13:00-14 :00 Non Noté	2%	Déjeuner buffet 2%	9%	8%	2%		1%
	SESSION RENCONTRE AVEC LE PERSONNEL PERMANENT ET NON PERMANENT
	Le comité se répartit en trois sous-groupes
	14:00 -14:30 Histogram		Rencontre avec les ITA titulaires , CDD
			Auditoire : membres du Comité, Délégué AERES, sans les Tutelles, ni la Direction, ni les
			responsables d'Equipes
	14:30-14:45		pause
	14:45-15:15		Rencontre avec les représentants de la Tutelle:
			Auditoire : membres du Comité, Délégué AERES
	15:15-15:30		Rencontre avec la direction de l'unité
			Auditoire : membres du Comité, Délégué AERES
	15:30-18:00		Réunion du comité à huis clos
	Short visit of the laboratory occupied team1. No unexpected event.

Présence : membres du Comité, délégué AERES 6  Statistics by field: SVE on 10/06/

 Supervising bodies' general comments

Université Paris Descartes, Vice--présidence du conseil scientifique, 12 rue de l'école de médecine, 75170 PARIS cedex 06

Téléphone: 01 76 53 17 45; Courriel: stefano.marullo@parisdescartes.fr