president Michel Cosnard

John Mclauchlan

This report is the sole result of evaluation by the expert committee, the composition of which is specified below.

The assessments contained herein are the expression of an independent and collegial reviewing by the committee.

Unit name:

Institute

Management team

The management team consists of Mr Thomas BAUMERT (director) and Ms Catherine SCHUSTER (deputy head).

HCERES nomenclature

SVE5 Physiologie, Physiopathologie, Cardiologie, Pharmacologie, Endocrinologie, Cancer, Technologies Médicales.

Scientific domains

The unit works on liver disease that are caused by viral infections (HBV and HCV mainly) and on aspects of virushost interactions. The main scientific interests of the unit have been firmly embedded in HCV infection and now expand to HBV. The key topics have focussed on: i) HCV entry; ii) the neutralization antibody response to infection, as this may influence development of a HCV vaccine; and iii) virus-host interactions that are critical for productive infection. The unit also has a strong translational element to transfer basic research findings for practical impact in the clinical arena. As would be expected during a 5-year programme, the unit's strategy has evolved to build on stronger elements from the technical expertise encompassed within the unit (for example, siRNA screens and mouse models) as well as opportunities arising from recruitment of younger programme leaders to refresh and develop the future scientific potential of the unit.

Unit workforce

UMR_S1110 was previously reviewed in 2012 by AERES with an overall excellent grading assessment and more recently in 2015 assessed as excellent by an international review committee who evaluated the LabEx component of the unit. The current review committee unanimously found the unit outstanding.

Over the past 5 years, the unit has cemented its international standing on studies on HCV infection with consistent outputs of outstanding quality in high-ranking journals (Nature Medicine, Cell Host & Microbe, Cell and Nature Biotechnology). In addition, it has engaged in a number of collaborative projects, and successfully obtained funding to support US and European collaborations. The international centres involved in these collaborations are internationally renowned for excellence in their own fields. This demonstrates the recognition of UMR_S1110 as a leading international institution in its own right and therefore the joint, collaborative studies should yield significant outputs in terms of publications. The unit should be commended for making the decision to broaden its scope outside of HCV for the next 5-year period, building on initial work on HBV and HDV that has already started and extending its interests to liver disease in general, whether of viral or non-viral origin. Finally, the unit has trained an impressive number of postdoctoral fellows and postgraduate students, and clearly offers a supportive environment for developing the next generation of young scientists.

The unit has identified possible issues with lack of space, delayed renovation and possible reduced funding for the biocontainment BioSafety Level 3 (BSL3) laboratory, which incorporates an animal facility, as areas that would affect its ability to attract new recruits. Such infrastructure support would be essential for the unit to retain its international standing as a centre of excellence. In addition, the plans suggested for the next funding period, although necessary for the unit to develop its scientific strategy in light of the success of new therapies to cure HCV infection, do present a risk. To expand the scientific portfolio and meet the proposed objectives, it is necessary that the unit has the ability to replace any key members of staff to maintain their competitiveness.

  location of the unit The Institute of Viral and Liver Disease (IVLD) is a mixed Inserm-University of Strasbourg research unit (UMR_S1110) located in Strasbourg. It was created in 2007 under the directorship of Mr Thomas BAUMERT as a PU-PH.

  of Viral and Liver Disease

	Unit acronym:	IVLD
	Label requested:	UMR_S
	Current number:	1110
	Name of Director (2016-2017):	Mr Thomas BAUMERT
	Name of Project Leader (2018-2022):	Mr Thomas BAUMERT
	Expert committee members
		Mr Théophile OHLMANN
	Representatives of supervising institutions and bodies:
		Ms Catherine FLORENTZ, Université de Strasbourg
		Ms Marie-Ange LUC, Inserm
		Ms Meriem MAROUF, Inserm
	Head of Doctoral School:
		Mr Serge POTIER, Doctoral School n°414, "Sciences de la vie et de la santé"

Chair:

Mr John MCLAUCHLAN, University of Glasgow, Scotland Experts: Mr Tarik ASSELAH, Université Paris Diderot Ms Birke BARTOSCH, CRCL, Université Claude Bernard Lyon 1 Ms Nathalie CALLENS, CIIL, Institut Pasteur de Lille and Université de Lille (representative of supporting personnel) Ms Jamila FAIVRE, Inserm, Université Paris-Sud Scientific delegate representing the HCERES:

signed by their chairman.by the chairman of the expert committee".


Report 1  Introduction Date and conduct of visit:

The visit took place on January 12, 2012 in the Forum of University of Strasbourg. The lab director gave first a general overview of the laboratory and a presentation of the scientific program. This was followed by short presentations of other staff scientists. The committee then met University and Inserm representatives, and split for separate meetings with PhD students/post-docs, technicians, and scientists.

It should be noted that Mr Matias Avila could not take part to the site visit.

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

This is a mixed INSERM-University research unit which is located in Strasbourg. It was created five years ago with the recruitment of Prof Baumert from Freiburg, Germany, with a position of PU-PH and head of the laboratory. This was part of the restructuration of a previous Virology INSERM Unit.

The research program of the unit is focussed on hepatitis C virus -host cell interactions, pathogenesis of hepatitis C infections, mechanism of viral entry, and discovery of viral entry inhibitors with the aim of providing innovative medicine for the treatment of hepatitis C in clinical practice. Definition and downloading of criteria: http://www.aeres-evaluation.fr/Evaluation/Evaluation-des-unites-de-recherche/Principes-d-evaluation.

Unit workforce:

 Assessment of the unit

Overall opinion on the unit:

The committee agreed that the unit has an outstanding activity in the field of HCV -host interactions at the level of both basic science and translational research. The director and his collaborators have created a unit which is internationally recognized in the field. The quality of the science, publications, fund raising and governance are excellent.

Strengths and opportunities:

The unit has developed all of the required technologies, study models and platforms to perform its research projects in a highly competitive manner. The unit's program is based on complementary approaches from basic science to clinical application and valorization.

Doubtless the unit is one of the world leading laboratory in the field of HCV entry inhibition. Their projects will be highly competitive and will provide important and new information on several aspects: 1) basic science knowledge of the mechanism of viral entry, 2) drug discovery and clinical trials of HCV entry inhibitors, 3) understanding of HCV pathogenesis based on translational research programs with application for liver transplant patients (prevention of graft infection). Moreover, their work on neutralizing monoclonal antibodies seems to be successful not only in acute infection but also in chronic infection models and is therefore promising in terms of clinical applications.

The unit has shown a large number of high quality results and has been extremely productive during the last evaluation period (publications in high ranking journals). As a result, the unit was able to recruit young talented researchers on INSERM or University positions.

The unit was also very competitive and successful in fund raising in the most competitive national calls (« investissement d'avenir ») and EU calls (ERC, InterReg).

Weaknesses and risks:

The unit proposal comprises a number of risky projects including a drug discovery and development project on HCV entry inhibitors, a program on host factor discovery in HCV entry, and the development of a mouse model, which all could lead to breakthroughs in the field. The quality of science and preliminary results render these projects realistically feasible. In any case, these projects will generate very important information on the biology of HCV and its interaction with its host. The unit is perfectly aware of these risks and has developed less risky projects for which preliminary results suggest a high level of feasibility.

No significant weakness was identified by the committee.

Recommendations:

The recommendation of the committee was to continue the same strategy.

 Detailed assessments

The unit presents a nicely integrated research program that is focused on the study of the pathogenesis of hepatitis C infections, the mechanism of viral entry, the discovery of viral entry inhibitors and is based on complementary approaches. The program has many clinical applications which follow well integrated translational studies.

Assessment of scientific quality and production:

The research program of the unit is focused on the study of HCV-host interactions, which is a very competitive research area. The unit is recognized as one of the world leading laboratories in HCV entry and pathogenesis due to highly relevant research and important contributions to the field of HCV infections. Recent seminal contributions of the unit include: (1) the discovery of viral entry and evasion from antibody responses as key factors for pathogenesis of liver graft infection; (2) the identification of specific cellular protein kinases as novel host factors regulating HCV entry; (3) the development of HCV entry inhibitors based on small molecule kinase inhibitors, as well as on neutralizing monoclonal antibodies targeting cellular HCV receptors. Characterization of the interaction of a viral nonstructural protein with apolipoprotein E and clarification of the role of neutralizing antibodies in viral clearance are further examples of important results with high international impact. Overall, the unit provides original and competitive research on the study of the mechanism of HCV entry and propagation and on the development of new entry inhibitors at the highest international level. The results are of highest impact on basic science with strong translational aspects, including the development of novel therapeutics based on own research, which will enter an investigator-initiated phase I clinical trial supported by INSERM and Roche.

The productivity of the research unit is outstanding, both in quantity and quality. Since 2007 the unit has published a total 109 original research papers in peer reviewed journals (42 directly from the unit with first and/or last author from the team), 31 (12 directly from the unit) with an IF > 5 and 20 (11 directly from the unit) with an IF > 10. The high international visibility is exemplified by recent publications in Nature Medicine (2011) and in the Journal of Experimental Medicine (2010), which were associated by comments and editorials in various journals and the media, and by two publications in PNAS (2007 and2008). The publication record furthermore includes a number of papers directly originating from the unit in top journals of the respective field like Gastroenterology, Hepatology, Journal of Hepatology and Journal of Virology. The unit is also keen to present its results to a broader community by contributing to a total of 45 review articles in peer reviewed journals including an article in Nature Reviews Microbiology (2010).

In summary, the scientific quality and production of this unit is outstanding, documented by a very large number of high impact publications.

Assessment of the unit's integration into its environment:

The unit is extremely well integrated into the local and regional research structures. Currently seven patent applications have been submitted, 50 contracts for materials have been signed, 12 company contracts and an OSEO award to create a start-up company have been received. The unit is excellently integrated in hospital structures such as the departments of Virology and Hepatology, but also in the University, enabling the set-up of an MD/PhD position as part of their Laboratoire d'Excellence award (Hepsys). As part of their research, a well-working collaboration with the "Institut de la Souris", Strasbourg, was established. One team member has an appointment within the Laboratory of Virology within the Hospital. Collectively, these links are extremely helpful in facilitating the translational research program of the unit. On the regional level the unit is a coordinating partner in the EU-funded Hepato-Regio-Net program linking the University of Strasbourg with Freiburg University and Basel University, and also part of the ERC Hepcent collaboration with the University of Heidelberg and Inserm UMR_S 758. The unit has additional funding as part of the Europrise network for HIV. ANRS funded collaborations include programs of "mouse models for viral hepatitis" and "HIV neutralising antibodies". This collaborative outlook has led to the unit being highly successful in attracting external funding which amounts to more than Eu10m (>Eu4m from European programs, >Eu4.5m from Science of Excellence « Investissements d'Avenir » programs and >Eu3m from National programs) from the last five years.

Their work is supported strongly by the University of Strasbourg with many staff positions including technicians and MCU-PH positions. Recently a CR1 position was obtained from INSERM (see also below).

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

The unit has an excellent national and international reputation. The director was awarded a "Chaire d'excellence" from ANR. The unit was successful in the highly competitive calls of the "Investissements d'Avenir" program since they were awarded a Laboratoire d'Excellence (LabEx) "Hepsys" and they are partner on another LabEX on HIV "VRI". Senior researchers have been invited many times to give lectures in international conferences or international institutions.

The laboratory is very attractive as exemplified by the training of in average 13 PhD students each year, 10 post-docs; but the unit has also trained 3 visiting senior scientists. Because of the high quality of research and funding from EU (InterReg program and ERC), approximately 2/3 of the trainees came from abroad.

As a result of the excellent quality of the research and scientific production as well as the performance of the trainees, the unit was able to obtain two recent researcher positions: one CR1 was recruited in 2009 at INSERM and one MCU-PH in 2011 at the University.

Based on an outsanding scientific reputation, the unit was able to join strong national networks supported by ANRS (HIV neutralization ; Hepatitis mouse model) and to establish international networks especially via EU funded programs (ERC, InterReg) or INSERM (European Associated Laboratory with Freiburg University). Furthermore, they have established 8 active international collaborations (examples : Rockefeller University, Tokyo, Scripps Institute, Birmingham University, Harvard University) with supporting publications.

Assessment of the unit's governance and life:

The unit's research program is based on a very well structured program with four thematic groups on virus-host interactions, lipoproteins and HCV life cycle, viral evasion and liver disease, HCV-HIV co-infections, and two platforms for animal models and for translational research.

There is strong leadership from the director, and one senior scientist has been promoted to deputy director of the unit. The management structure is well organized comprising a Unit Board (Conseil de laboratoire) which includes representatives from all levels within the unit. The unit further has a good internal and external communication strategy.

Scientific activity is well stimulated as shown by the quality of the outputs. Specifically the unit meetings are supplemented by a bi-weekly journal club, monthly invited speakers and scientific symposia, which are integral to the European grant structures. Additional educational activities include undergraduate laboratory training, seminars for the general public and media releases.

The depth of funding allows the group to be able to take a number of risks. This is best illustrated by the the mouse models of HCV infection, which is a challenging project. To address the risk the group has set up scientific collaboration with a well-known expert group, and having several contingencies, they are including alternate models to increase the probability of project success.

To supplement the unit's educational needs there are weekly unit meetings, weekly thematic group meetings, monthly working group and staff scientist meetings and bi-annual unit board meetings. They are involved in structuring regional research through the trans-border FP7 funded InterReg program linking Strasbourg with Freiburg and Basel.

Assessment of the strategy and 5-year project:

The unit presents an excellent 5 year research program with very original and relevant projects that are highly competitive. The major strength is a comprehensive implementation of key technologies, expertise and models that have been established by the laboratory, including access to a high throughput screening platforms, clinically relevant animal models and patient cohorts. Combined with well documented cooperations with other world leading laboratories, the unit provides a highly integrated unique and powerful center of translational HCV research, which will be further developing within the future. The excellent infrastructure and a very strong governance with outstanding fund raising (>10 Mio €, including long term funding) and consistent allocation of human resources and budget for consumables and equipment are further keys to excellent future perspectives of this unit.

The scientific research program primarily aims to study virus host interactions and to develop innovative medicines for HCV targeting viral entry in a translational research effort. Preliminary unpublished work in animal models suggests that this strategy is effective in combination with other drugs developed by the pharmaceutical industry targeting different steps of the viral life. The program follows 6 axes:

1) Virus -host interactions (viral entry) :

Recent findings of the unit showed that SR-B1, CD81, CLDN1 but also EGFR and EphA2 are host factors for hepatitis C virus entry. The importance of these findings is well illustrated by a number of high ranking papers, including Hepatology and Nature Medicine. The group will analyse the underlying signal cascades. Genome-wide analysis of protein kinases involved in entry already showed multiple hits, which is in agreement with findings on other viruses. Logically the unit proposes a research project, which allows to identify the order and the molecular interactions of the complex pathway. Such analyses will shed light on specific fundamental processes of HCV. Very probably the results will be of high interest not only for this particular virus but also on the entry of other pathogens entering the cell by similar mechanisms. Moreover, this research project has an additional strong translational element in that protein kinases specific for HCV will be used as drug targets. The elaborated techniques and systems present in the unit will strongly support the success of the project. Eventual risks in the finding of successfully applicable drugs are perfectly counter-balanced by the strong impact of the fundamental part.

2) The role of lipoproteins in HCV life cycle. Assembly of infectious HCV virions is still poorly understood, since efficient model systems have been available for a short time only. The unit recently identified an important link between viral proteins and the lipid metabolism network of the host cell by showing that apolipoprotein E (apoE) interacts with the viral nonstructural protein NS5A. The future research aims are directed towards an understanding of the mechanistic role of apoE in the viral life cycle. The unit has established a cell line devoid of apoE expression, which is permissive for HCV entry and replication but impaired in virion production. By expression of distinct apoE mutants this important tool will allow a functional characterization of apoE in viral assembly. Complementary to this approach, the unit has defined certain parts of apoE involved in entry, particularly the heparan sulfate binding domain (HSPG), which might allow the development of inhibition strategies based on HSPG mimetic peptides. This work is funded by LabEx HEPSYS, ANRS and two PhD fellowships from ANRS and MRT and will clearly deliver important novel insights into the functional role of apoE in HCV replication. Furthermore it has the potential to identify novel anitiviral strategies targeting entry, assembly and release. Virions with defined apoE mutant will also allow to address functions of lipoproteins in evasion from B-cell responses.

3) Viral evasion and liver disease. Mechanisms involved in the establishment of viral persistence and underlying viral pathogenesis are still ill defined. Previous work of the unit already unraveled the role of viral escape to neutralizing antibody responses and the complex contribution of innate and adaptive immune responses to protective immunity against HCV. The future aims of this project are directed to a better understanding of counterregulatory mechanisms engaged by HCV to evade functional immune responses, to gain closer insights into viral persistence and pathogenesis. This work will be focused on HCV neutralization and evasion from B cell responses by uncovering viral epitopes and entry factor domains targeted by antibodies. The unit will also investigate the impact of lipoproteins in evasion from B cell responses by testing apoE mutants and implement screening approaches to identify common host factors of antibody-mediated neutralization. A complementing approach will decipher counterregulatory mechanisms restraining HCV-specific cellular immune responses, particularly addressing indoleamine 2,3-dioxigenase (IDO), a host gene which is upregulated in acute and chronic HCV infection. The project aims to investigate the molecular mechanism of IDO induction in HCV infection and its impact on HCV clearance and antiviral T-cell response by siRNA mediated silencing and overexpression of regulatory molecules of known IDO pathways. The research plan on viral evasion and liver disease is well feasible and embedded in top-level international research networks receiving funding from ERC and Hepato-Regio-Net.

4) HCV-HIV coinfection.

Co-infections with HCV and HIV are common, particularly among injection drug users. HIV elite controllers seem to better control HCV infection as well, in part due to stronger T-cell responses. The project aims to unravel the additional contribution of neutralizing antibody responses against HCV. By taking advantage of a unique cohort of HIV elite controllers, anti-HCV antibodies will be analyzed in HCV co-infected patients compared to HIV progressors and HCV monoinfected individuals. If improved HCV specific antibody response is associated to a better control of HCV infection epitope specificity and subtypes will be determined, as well as phenotypic distribution of B cell subpopulations. The project furthermore aims to gain insights into mechanisms of HCV/HIV immunopathogenesis by correlating humoral immune responses against HCV with outcome of infection and disease progression. The work is supported by funding from ANRS, API Hopitaux Universitaires de Strasbourg, Eurorise, LabEx VRI and Euronet-41. The project follows a clearly defined strategy and could lead to development of immunotherapeutic approaches allowing control of HCV infection and/or delaying progression of liver disease.

5) Development of immune competent mouse models for HCV infection.

Such a model would represent a major breakthrough in HCV research and would have a strong impact on our understanding of HCV pathogenesis, studies on immune evasion, vaccine development and provide perspectives to study co-infections of HCV with HBV or HIV. The unit has already established the current state of the art immune deficient mouse model based on uPA SCID mice reconstituted with primary human hepatocytes, allowing to study virus entry, replication and drug development. One strategy of the research program aims to reconstitute a human immune system in this model by transplanting CD34+ hematopoetic stem cells. An alternative approach aims to generate transgenic mice susceptible to HCV infection. Currently the determinants of HCV entry into mouse cells are well understood and transgenic mice expressing human entry factors are in development. However, some host factors required for efficient viral RNA replication seem to be missing in mouse cells and the project aims to identify such factors by library screening approaches in mouse cells. Both approaches involve collaborations with other internationally leading laboratories and are funded by grants from ERC, Investissements d'Avenir, ANR and ANRS.

6) Translational medicine with clinical trials and pathogenesis studies.

A major strength of the unit is the availability of patient cohorts and research platforms allowing a streamlined transfer of research data into translational approaches. All of the above projects will generate data and approaches either leading to potential novel antiviral strategies or addressing virus-host interactions involved in pathogenesis, both contributing to the translation research pipeline of the unit. Hallmarks of the translational approach are the identification of key mechanisms of liver graft infection and viral persistence and investigations on the clinical impact of virus-host interactions for liver disease. This approach involves unique and huge patient cohorts available through clinical partners and research networks and is supported by the ERC and EuroNet-41. A second translational effort is aiming to develop first-in-class viral entry inhibitors and vaccines for prevention and treatment of HCV. Most advanced is an investor-initiated clinical trial on the HCV inhibitor Erlotinib starting in 2012/2013, funded by industrial partners and Inserm. This approach is a direct spin-off from the basic research of the unit, demonstrating the comprehensive and interdependent overall strategy. Further mid-and long-term clinical projects are based on the inhibition of HCV entry using monoclonal anti-receptor antibodies, which have been very efficient in a small animal model. Although development of anti-HCV therapies is highly competitive and therefore these projects are risky, the implementation of these research programs will strengthen the visibility and clinical impact of the unit and pave the road for new long term projects, probably focusing also on alternative pathogens and diseases.

Overall the research program is very consistent with complementary approaches from cutting-edge basic science to translational research and clinical trials. Projects and scientists within the unit are highly interdependent providing a synergistic research group. Some projects are risky, particularly due to the high competition in the research area. The efforts on drug discovery are facing a high competition for HCV drug development driven by the pharmaceutical industry. The inhibitors of viral entry could be used in combination with other drugs developed by the pharma industry which are targeting other steps of the viral life cycle. The innovative nature of the approaches will also provide new and cutting-edge information on HCV pathogenesis and develop into new models to perform translational research. In case of success this approach will be highly beneficial, particularly for patients who are difficult to treat like those suffering from cirrhotis and treatment experienced patients. Development of immunocompetent small animal models is also highly competitive and competing laboratories might be faster. Still, the need for such a model to understand antiviral immune responses and pathogenesis clearly justifies the risk, particularly due to the huge number of potential applications. Overall, the risk-taking is fully appropriate and warranted by the high impact of research results in case of success. The research program furthermore includes a number of excellent and relatively safe projects building on extensive preliminary work, like the further characterization of signaling events upon viral entry, which will help to backup failures to achieve the ambitious goals.

Of particular importance for the translational efforts of the unit is the recruitment of an excellent clinical hepatologist to replace the current head of the hepatogastroenterology department who will retire in 2 years.

 Grading

Once the visits for the 2011-2012 evaluation campaign had been completed, the chairpersons of the expert committees, who met per disciplinary group, proceeded to attribute a score to the research units in their group (and, when necessary, for these units' in-house teams). This score (A+, A, B, C) concerned each of the four criteria defined by the AERES and was given along with an overall assessment.

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

 Overall assessment of the unit :

Virus-host interactions and liver disease

Excellente unité à tous points de vue.

Grading table:

C1

Scientific quality and production.

C2

Reputation and drawing power, integration into the environment.

C3

Laboratory life and governance.

C4

Strategy and scientific project.

A+

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

  A+ A+ A+ 5  Statistics per field : SVE au 10/05/2012

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

Assessment of the unit's involvement in training:

The unit participated very well in the training of students and postdocs on different levels. From 2007 to 2011 27 Master 1, 14 Master 2 were trained in the unit. Seven PhD students and 2 MD students passed their thesis, in addition to 4 "habilitations à diriger des recherches". All students were 100% financed by different sources including the French Minister of higher education but also by 3rd party money. Advancement of the theses is verified by midterm reviews; the maximal duration of PhD thesis was 3.5 years. The students are represented in the unit's "conseil de laboratoire" and participate in the design and analysis of unit's projects. All students have a permanent partner on the level of the lab and -if required -daily access to the PI. They participate at weekly meeting on the unit level but also on thematic group meetings. The students communicate their results on all levels including international conferences. They further participate in meeting organizations, including the annual Biotechnology forum of Strasbourg. The good career development strategy of the unit is documented by the positions of the students after finishing their thesis, which comprises high-level academic institutions as Stanford and Harvard Medical School, University of Pennsylvania but also in industry (Gilead, Nycomed, Covance, Biomérieux). In the name of the collaborators, members and clinical partners of Inserm unit UMR_S748, I would like to thank the AERES visiting committee for the site visit. We acknowledge the thorough and detailed evaluation and appreciate the very positive comments of the committee.

We are aware that it is of particular importance for the clinical unit program to recruit a clinical hepatologist to replace the current head of the Hepatology-Gastroenterology service at the Strasbourg University Hospital who will retire in 2014. We would like to inform the AERES that the preparation of the recruitment through the Faculty of Medicine of the University of Strasbourg is ongoing.

Professor Thomas Baumert, MD Head, Inserm unit UMR_S748


The visit took place on the 13 th of January at the school of medicine. Dominique Guénot presented during 45 minutes the past activities of the previous teams and the project of the new team. The co-director of the team presented some clinical aspects emphasising on the future creation of the Institut Régional du cancer in Strasbourg. Then a discussion was held with the participation of all the team members. Thereafter the panel split and met separately students and post-docs, technicians, and scientists in the absence of the team leader.

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

The project corresponds to the fusion of 2 university teams, EA 4438 (D Guenot) and EA 3430 and 2 small teams attached to the school of medicine, in the field of haematology and of biostatistics. The objective of the project is to gather the strengths in oncological translational research in a unique team. This new team will benefit of the molecular oncology platform labelled by INCa, which participates to the project and of clinical facilities of the CHU and Paul Strauss Comprehensive Cancer Centre. This demand of creation is part of and complementary to the ambitious project to set up in Strasbourg the "Institut Régional du Cancer d'Alsace", which will group in a new building in 2017 the oncological activities of Paul Strauss Centre and the CHU with research teams located in its vicinity.

Today, the teams are localized in different sites in Strabourg; the Paul Strauss Cancer Center and the University Hospital. The biological part of the future team will aggregate on a single location at the hospital in 2013 and the biostatistics and epidemiologic part will rejoin the hospital site in 2015.

The team develops cancer research projects from basic to translational and clinical research including epidemiology. The research programs rely on biological resources and molecular oncology platform, bringing observations to basic research. The central theme of the team is the understanding of the role of hypoxia and the microenvironment in tumor progression and the response to treatment.

Management team:

The team is directed by Dominique Guenot, a Scientist at the CNRS and co-directed by Georges Noel, a radiotherapist at Paul Strauss Cancer Centre. Overall opinion on the unit:

Workforce

The project of creation of this new team is to gather 2 university teams that have developed common strategies in translational cancer research reinforced by 2 teams from the medical school in the domain of hematology, epidemiology and biostatistics. They brought relevant contributions in at least 3 fields; biomarker discovery for many cancers, discovery of determinants of the response to radiotherapy, and clinical trials. Each of these units has produced good quality work, has a high level of productivity overall, although not outstanding in terms of high impact publications and not sufficiently visible for providing an international recognition. They rely on the molecular oncology platform labelled by the INCa that provides access to biological samples and molecular technologies. The ambition is to create a reference research team in translational cancer research in the perspective of the creation of the Regional Institute of Cancer in Alsace, allowing the concentration of human, technical and financial resources. This is a great objective and it should be continued. They propose a scientific project, which considers the past project from each team, focusing on a relevant common theme on the role of hypoxia and microenvironment in tumor progression and response to therapy. However, it seems that the reflection was not conducted until the end because there are still too many projects for the team to be competitive at the international level. Moreover, the involvement of the biostatistics and epidemiology teams should be clarified, and possibly more directly related to the particular focus of this new research team. It seems necessary to focus on fewer projects to allow the development of more competitive programs in which basic research should be reinforced.

Strengths and opportunities:

They have a long experience in translational cancer research leading to contributions to the discovery of new biomarkers. They develop clinical research funded by grants obtained from competitive call for proposal (PHRC). It has been established effective and productive collaborations between the research groups, the molecular oncology laboratory including the Centre for Biological resources, the technological platforms and the clinics. This is facilitated by the participation of MD and PharmD to the team. They have a strong involvment in students teaching, medical training in research and academic promotions of their collaborators.

The main opportunity is the future creation of the "Institut Régional du Cancer d'Alsace" permitting to build a trans-institutional ambitious project in translational research. Integration of biostatisticians could be an added value to the team through a better definition of their implication in the project.

Weaknesses and risks:

The number of post-docs and full time researchers involved in basic project is too low. The location on 2 different sites is not favorable for building this new team.

The dispersion is a major risk for the competitivity of the team by lack of resources allocated to projects, and it could ultimately impair the success in national calls, which are important providers for funding.

Recommendations:

Choose the most competitive projects and allocate to them adequate resources. This implies to continue the reflection on the building of an ambitious project for the team.

Prioritize the recruitment of post-docs to support experimental research programs and implement a strategy to attract or recruit permanent researchers in the next 5 years.

The regroupment on the same site of the different partners of the team should be realized in 2013 as mentioned.

 Detailed assessments

Assessment of scientific quality and production:

For the past activity, the group of Mr GUENOT (EA4438) has been focused on "molecular markers of tumor progression and sensitivity to anticancer drugs". This group performed its research in epithelial cancer cells by conducting fundamental and pre-clinical approaches, which have led to a better understanding of some mechanisms of carcinogenesis in several models of cancer such as colon, lung adenocarcinoma in never smokers, pediatric brain and osteosarcomas.

The group from EA3430 has developed a research program on genetic alterations of cancer and modulation to the response to radiation therapy. They mainly focused their activities in metastatic progression, molecular basis of the response of cancer cells to radiation therapy, and its pharmacological modulation using both head and neck squamous cell carcinoma (HNSCC) and hepatocellular carcinoma models. They did make optimal use of availability of well documented tumor samples and do have translational relevance.

The other groups from the school of medicine, notably the epidemiologists, presented also a good record of publications, although weak in biostatistics.

The groups have produced good quality work. They have a high level of productivity overall, although not outstanding in terms of high impact publications. They published 132 publications in international journals and the average impact factor is 4.9. Overall, the impact factors of the publications are quite modest and could be improved. The number of publications with a present or past team member in a relevant position as first or last author is 43. The most important publications of the team are published in Int. J. Cancer, Clin Cancer Res, J. Proteome Res and Breast Cancer Res Treat. Only 3 biostatistical publications were found including one in Statistics in Medicine, which ranks 8 th in the field.

Assessment of the unit's integration into its environment:

Economic valorisation does not seem to be the priority of the team and some efforts should be made on that direction, although they are concerned about the translation of their results into the clinic. Links to clinical activities is positive and particularly relevant for access to clinical samples and possibility to run clinical trials.

The team is really efficient to raise funds due the high number of clinicians involved in the team (1500 K€ coming from clinical PHRC projects (34%), private (18%) and INCA (39%). However, the financial support coming from the basic research part does not seem to be consequent, which raises the question of the team competitivity in that regards.

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

There are no prizes and distinctions reported for the team regarding its significant contribution in the scientific national and international community. The recognition seems to be limited to the Grand Est Canceropôle mainly for their two platforms "xenograft for pre clinical studies" and "quality of life and cancer".

Mostly local, regional and national collaborations are mentioned. There is none or minimal emphasis on international collaborations, despite the fact that these research topics are widely studied.

The capacity of the team to recruit researchers, post-docs and high-level students, in particular from abroad has not been mentioned by the team and does not seem to be easy.

The clinicians seem to have good national network as it is demonstrated by their PHRC and INCa's network projects. The recognition of the team in the international community is weak as it is reflected by the low number of collaborations and invitations with the international laboratories and institution. There is no mention to participation to international programs, visiting fellows or exchange programs. This also applies to the methodological setting of phase I clinical trials, with no scheduled collaboration elsewhere.

There is no visible national or international impact. This could be improved.

The future director of the team has been able to set up discussions to propose a project regrouping 4 groups coming from different institutions with their own research themes and this must be noted. She is well accepted and recognized as the leader by the other members of the team. Moreover, they establish an organization that allows scientific communication and educational activities.

However, discussions should continue to select the most competitive projects and to prioritize those ones for the next 2 years.

Assessment of the strategy and 5-year project:

For the next 5 years, the team proposes to work on projects related to hypoxia and microenvironment in tumour progression and response to treatment. These projects are grouped into three main axes related to tumor adaptation to hypoxia (axis 1), hypoxia and microenvironment in tumour dissemination (axis 2) and hypoxia and chemotherapy/radiotherapy resistance: preclinical models (axis 3).

The project is fully relevant and of importance in the field. The access to clinical samples and the molecular biology platforms are clear added values.

The topics are articulated in a series of 12 sub-projects, certainly too many. Some projects are better defined than others, with clearly defined objectives and experimental plans. However, others are barely sketched and do not provide the essential information needed to understand what is specifically proposed to be done. A major criticism for some of them is the lack of originality and innovative approaches. While the relevance of the various projects sounds very good and well structured, the adequacy between manpower and real time implication for the clinicians to develop their research is questionable.

Assessment of the unit's involvement in training:

The involvement of the unit members in educational activities is pretty good due to the high number of professors (5) or MCU-PH (5). Student recruitment (PhD) is good (7 in 4 years) for the size of the team, no track of post-doc training.

They also seem to be quite well involved in regional animation as demonstrated by Canceropole Grand-Est certifications. Reputation and drawing power, integration into the environment.

Laboratory life and governance.

Strategy and scientific project. Overall, we agree with the general comments of the AERES report but we have few points that we would like to discuss:

A+
1-We feel that the committee expected a scientific report of the unified activity of our four teams, with aims consistent with each other. We would like to stress out that the project we submitted presents the strategic research axes as we envision them in the next five coming years. It must be precised that up to now, these four teams had little worked together and it is only recently that common projects have been built on.

2-Page 6: "The team is really efficient to raise funds due the high number of clinicians involved in the team (1500 K€ coming from clinical PHRC projects (34%), private (18%) and INCA (39%). However, the financial support coming from the basic research part does not seem to be consequent, which raises the question of the team competitivity in that regards." We clearly emphasized that our projects -past and coming -are essentially translational projects rather than basic research and justified the fact that we were funded by the INCa but also by the Ligue Contre le cancer. We consider that our strength relies on the models that we developed to ensure a high quality translational research. However, we take the opportunity of several collaborations with teams of high quality for basic research, in Strasbourg, as with the IGBMC for instance.

3-Page 6 : « Overall, the impact factors of the publications are quite modest and could be improved". All publications consisted of 132 articles in international journals with peer-review. Consequently, it is not easy to publish as many articles in journals of high impact. On the other hand, there is in this list of publications, some relating to biostatistics and epidemiology. In these subjects, the journals concerned do not have high impact factors.

Madame Dominique GUENOT

5

  Statistics per field : SVE au 10/05

  2012 AERES reportTumour progression and microenvironment Translational approaches and epidemiology -D. Guenot

TOTAL N1 to N7 29 20 * If different, indicate corresponding FTEs in brackets.

			Number on 06/30/2011	Number on 01/01/2013	2013-2017 Number of
					producers**
	N1: Professors or assistant professors	10	10
	N2: EPST or EPIC researchers	2	1	1
	N3: Other professors and researchers	4	4	4
	N4: Engineers, technicians and administrative staff *on a permanent position	5	5
	N5: Engineers, technicians and administrative staff * on a non-permanent position	2
	N6: Postdoctoral students having spent at least 12 months in the unit	1
	N7: Doctoral students	5
	N8: PhD defended		5
	N9: Number of Habilitations to Direct Research (HDR) defended	3
	N10: People habilitated to direct research or similar	9	9
	**	Number of producers in the [01/01/2007-06/30/2011] period who will be present in 2013-2017.
		Definition and downloading of criteria:
		http://www.aeres-evaluation.fr/Evaluation/Evaluation-des-unites-de-recherche/Principes-d-evaluation.

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

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

 Grading

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

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

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

 Overall assessment of the unit :

Tumour progression and microenvironment. Translational approaches and epidemiology

Unité dont la production, le rayonnement et le projet sont bons, mais pourraient être améliorés. L'organisation et l'animation sont très bonnes.

Grading table:

C1

Scientific quality and production.

C2

Reputation and drawing power, integration into the environment.

C3

Laboratory life and governance.

C4

Strategy and scientific project.


president Michel Cosnard

Evaluation report

This report is the sole result of evaluation by the expert committee, the composition of which is specified below.

The assessments contained herein are the expression of an independent and collegial reviewing by the committee.

Unit name:

Biology and pharmacology of blood platelets: haemostasis, thrombosis, transfusion

Unit acronym:

Label The INSERM U 949 located in "l'Établissement Français du Sang" (EFS) Alsace-Lorraine-Champagne-Ardenne (ALCA) and directed by Mr Christian GACHET was created on 1 st January 2009, as the successor to the U 311 previously created by Mr Jean-Pierre CAZENAVE in 1986. U 311 was recreated in 1999 and directed by Mr Christian GACHET since 2002. The group is composed of two complementary and interactive teams: team 1, entitled "Biology and pharmacology of blood platelets" under the direction of Mr Christian GACHET; and team 2, entitled "Biology of thrombopoiesis" under the direction of Mr François LANZA. Research undertaken at this unit is both multi-and inter-disciplinary in nature and includes cutting-edge thrombosis and haemostasis laboratories, platelet production laboratory, animal facility and electron microscopy platform. Work is carried out in collaboration with the University of Strasbourg, University Hospital of Strasbourg and EFS.

Management team

Over the course of the contract, Mr Christian GACHET was the director of the research unit and was appointed director of EFS-Alsace in 2013.

HCERES nomenclature

SVE5 Physiologie, Physiopathologie, Cardiologie, Pharmacologie, Endocrinologie, Cancer, Technologies Médicales SVE2 Biologie Cellulaire, Imagerie, Biologie Moléculaire, Biochimie, Génomique, Biologie Systémique, Développement, Biologie Structurale

Scientific domains

The general research aims of the unit are to develop a better understanding of the molecular and cellular mechanisms controlling platelet production and function, mainly in the context of thrombosis and haemostasis, although there is an increasing drive to investigate the roles of platelets in other pathophysiological processes, including inflammation and cancer, and to improve transfusion safety of blood products. The primary areas of investigation are inter-related and a major part of the work is devoted to transfusion research and medicine.

Unit workforce

Global assessment of the unit

The overarching research objectives of UMR-949 are to better understand the cellular and molecular mechanisms regulating platelet production and function, and to improve transfusion safety of blood products. To achieve these objectives, the group is divided into two teams with distinct and overlapping research interests. The main scientific interests of team 1 are: (i) to determine the molecular mechanisms regulating platelet function, mainly in the context of thrombosis and haemostasis, but also in inflammation and cancer; (ii) to identify and validate novel anti-thrombotic drug targets found in platelets; and (iii) to devise safer ways of preparing blood products for transfusion into patients. The main scientific objectives of team 2 are: (i) to elucidate how platelet progenitors called MegaKaryocytes (MKs) develop; (ii) to determine the cellular and molecular mechanisms controlling proplatelet formation and platelet production; and (iii) to devise new and improved ways of culturing MKs outside of the body in order to produce platelets in sufficient quantity and activity that they can subsequently be transfused into patients, thus improving patient safety. There is added value in the two teams working together as evidenced by the number of shared outputs, which should continue.

Since the last evaluation in 2012, outputs of the unit as a whole, scientifically, academically and translationally have been outstanding. The unit has published several landmark studies in leading clinical-scientific journals in the fields of cardiovascular and experimental medicine, thrombosis and haemostasis, and transfusion medicine. The success and esteem with which the unit is regarded is evidenced by numerous invited and selected presentations at both national and international meetings and conferences, hosting of national and international meetings, as well as hosting of leading scientists and trainees from around the world.

  spent at least 12 months in the unit 7 Number of Research Supervisor Qualifications (HDR) obtained during the period

signed by their chairman.


president Michel Cosnard

André Goffinet

Evaluation report

This report is the sole result of evaluation by the expert committee, the composition of which is specified below.

The assessments contained herein are the expression of an independent and collegial reviewing by the committee.

Unit name:

Experimental In the first 5-year period (2012-2017), three teams were integrated. The organisation will be unchanged for the next 5 year period (2018)(2019)(2020)(2021)(2022).

LNEC is located in the building of the "Pôle Biologie-Santé" of the University of Poitiers. The building also hosts one CNRS unit working on ion channels, two university teams and two INSERM units working in kidney ischemia and in pharmacology. LNEC and those other research units share large equipment and facilities, especially a state of the art animal facility (Prebios) and an imaging platform (ImageUp), which are located in the same building.

Management team

Mr Mohamed JABER is the founding director of LNEC since 2013 and is proposed to remain director for the new contract period (2018)(2019)(2020)(2021)(2022). In addition to the scientific evaluation of the three teams, which rates the research output as excellent to outstanding, the unit was also evaluated globally and it was concluded that the management structure is very efficient, that the budget required for this management is very well balanced, and that the unit provides a very useful and favourable environment to the three participating teams. This concerns laboratory space and accommodation as well as the availability of technological platforms and collaboration with other biomedical and clinical teams in the same building or in close proximity. Funding of the unit proceeds mostly from French and regional sources more than international agencies and reveals very good fundraising ability (3 FEDER, 4 ANR, 4 FRM and 4 Fondation de France grants). The research of the teams is focused on neuroscience and includes: development of cellular therapy in brain repair, mechanisms of relapse in addiction, the physiopathology of Parkinson disease and dopa-induced secondary effects, the physiopathology of autism spectrum disorders with an original focus on the role of locomotor systems. Members of the unit are also involved in training students and junior researchers (10 PhD students, but also about 4 M2, 5 M1 and 9 bachelor students per year). These research themes are very important considering their societal impact, and the different research groups in the unit work in close coordination.

  location of the unit LNEC is a mixed research unit INSERM-University of Poitiers that was created in 2012.

  Biologie Cellulaire, Imagerie, Biologie Moléculaire, Biochinime, Génomique, Biologie Systémique, Développement, Biologie Structurale SVE5 Physiologie, Physiopathologie, Cardiologie, Pharmacologie, Endocrinologie, Cancer, Technologies Médicales Scientific domains LNEC is following three axes of research to study neural repair through cellular therapy, mechanisms of drug addiction and brain circuitry in brain diseases especially in the locomotor system. spent at least 12 months in the unit 7 Number of Research Supervisor Qualifications (HDR) obtained during the period 2  Assessment of the unit Global assessment of the unit

  and Clinical Neurosciences Laboratory

	Unit acronym:	LNEC
	Label requested:	UMR
	Current number:	1084
	Name of Director	Mr Mohamed JABER
	(2016-2017):
	Name of Project Leader	Mr Mohamed JABER
	(2018-2022):
	Expert committee members
	Chair:	Mr André M. GOFFINET, Université de Louvain, Belgique
	Experts:	Ms Colette DEHAY, Université Claude Bernard Lyon
		Ms Laurence DESRUES, Université de Rouen (representative of the supporting
		personnel)
		Ms Isabelle DUSART, Université Pierre et Marie Curie (representative of the CNU)
		Mr Stéphane HUNOT, Institut du Cerveau et de la Moelle Épinière (representative
		of the INSERM CSS)
	Scientific delegate representing the HCERES:
		Mr Jacques NOËL
	Representatives of supervising institutions and bodies:
		Mr Serge HUBERSON, Université de Poitiers
		Ms Marie-Louise KEMEL, INSERM
	Head of Doctoral School:
		Mr Gérard MAUCO, Doctoral School N°524, "Bio-Santé"