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Current treatments for retinoblastoma, the most common intraocular malignancy, rely on a limited number of drugs repurposed from other pediatric cancer therapies. Drug toxicity and relapse of the disease necessitate new therapeutic strategies. The implementation of drug candidates in the clinic is usually followed by in vitro validation, which requires accurate and clinically relevant in vitro models. We report here a robust 3D tumoroid-based platform, for testing various clinical protocols, e.g. therapeutic agents following a single or repeated exposure, alone or in combination with focal therapy (thermotherapy). The platform, generated from the Y79 retinoblastoma cell line, consists of matrix-embedded tumoroids, which retain the key features of the disease and allow prolonged culture time. Following the optimization of growth conditions, the effect of single and repeated exposure to chemotherapeutic agents has been measured by high-throughput automated fluorescence imaging followed by quantification. The clinical conditions of chemothermotherapy have been recapitulated with a setup consisting of: an infrared diode laser (810 nm, 0.3 W) that heats the tumoroids in the presence of indocyanine green (50 µg/mL); a thermal camera to enable real-time temperature measurement; and an environment-controlled inverted microscope to ensure physiological conditions and precise focusing of the laser. Melphalan and carboplatin, two drugs currently used to treat retinoblastoma in clinical protocols of chemotherapy and chemothermotherapy respectively, have been applied to validate the system.Tumoroid viability and size progressively decreased over 4 weeks of repeated drug exposure with melphalan, reflecting the response of retinoblastoma in advanced clinical cases. Carboplatin treatment showed an activity enhancement in the tumoroid model similar to that observed in the clinic, when combined with focal therapy, demonstrating that the platform system closely recapitulates the clinical conditions. Inversely, the thermotherapy experimental protocol designed for 2D in vitro cell culture and commonly used to date, i.e. an incubation temperature increased to 42 °C for 1 h, did not show an improvement of the carboplatin cytotoxicity, confirming that our laser-based thermotherapy protocol provides a more accurate and clinically relevant drug response. Such an approach, combining physiologically relevant in vitro cancer models and investigation of drugs in well-established treatment modalities, can significantly reduce the number of new drug candidates that give false-positives or overestimated efficacies when evaluated in relevant in vivo models. It is expected that the platform will contribute to the implementation of new therapeutic strategies to treat retinoblastoma, and could also be adapted to other diseases for which repeated drug exposure and/or chemothermotherapy is relevant. Citation Format: Irina Sinenko, Fabien Kuttler, Valentin Simeonov, Alexandre Moulin, Christina Stathopoulos, Gerardo Turcatti, Adeline Berger, Francis Munier, Paul Dyson. Tumoroid-based screening platform to test focal, chemo- and combination therapy for retinoblastoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3541.

In this chapter, we study the relationship between innovation and happiness. After a philosophical detour showing a distinction between quiet and wild innovation, we examine the methodological aspects in the analysis of the impact of innovation on subjective well-being. We then propose a review of the literature, also focusing on the link between creativity and happiness as source of innovation.

In this chapter, we propose a focus on a particular technology that invades more and more our lives: ICT. The effects of ICT use are well documented. A review of the main empirical results is presented to show that especially the use that matters in terms of impact on happiness.

One type of innovation that seems quite promising to reconcile innovation and positive impact, especially on happiness, is frugal innovation. We present here the ins and outs of this innovation in terms of well-being.

In this chapter, we study the relationship between technologies and happiness. We study the ambivalent side that technology can also induce, in the sense that it brings a lot of comfort and progress in many areas, but what about the possible impacts on the well-being of individuals.

This chapter summarizes the main results of the previous chapters in order to propose a new concept, that of Positive Innovation, allowing for a happy medium between innovation and happiness.

Here we discuss two particularly interesting and appropriate approaches for taking into consideration the impacts of innovation on the individual, and even his happiness. The first is more a practice initiated by the EU, the second a philosophical approach.

We study two concepts inviting the individual to free himself from a too important prevalence of technology and to find a good life, beyond the material comfort, it is the concept of creative goods and resonance.

Since we are interested in the impact of technology on happiness, it seems useful to us to look at the question of transhumanism and artificial intelligence. Finally, isn’t the augmented indivdual also a diminished humanity?

Rare Vascular Diseases (RVD) encompass different types of vessel involvement. Some cause a dilation, others a weakening or tortuosity of the arterial wall, others an obstruction or excessive calcification of arterial walls. Clinical pathway of patients with RVD to diagnosis is often long and complex. Thus, in order to allow early diagnosis and coordinated multidisciplinary management and follow-up, a specialized RVD centre has been set-up at the CHUV, following the framework of the national concept of rare diseases.Les maladies vasculaires rares (MVR) englobent différents types d’atteintes des vaisseaux. Certaines engendrent une dilatation ou une tortuosité de la paroi artérielle, d’autres une fragilisation de la paroi, d’autres encore entraînent une obstruction du vaisseau, une calcification excessive des parois, ou des malformations vasculaires. Comme pour toutes les maladies rares, le parcours des patients vers un diagnostic est souvent long et complexe. Afin de permettre un diagnostic le plus précoce possible, ainsi qu’un suivi coordonné et une prise en charge multidisciplinaire médicale et sociale, un centre des MVR a été mis en place au CHUV, dans le cadre du concept national des maladies rares.

Depuis la reforme de l’annee 1978, la performance economique de la Chine a ete remarquable. Neanmoins, un nouveau tournant apparait et certaines questions se posent. Le taux de croissance de la Chine peut-il continuer a ce rythme ? La Chine doit-elle abandonner son modele historique fonde sur de faibles couts de main-d’œuvre ou plutot s’orienter vers la creativite ? Est-ce la bonne voie pour maintenir a la fois la croissance quantitative et ameliorer la qualite de vie des citoyens ?Le but de notre article est de montrer que le passage du « Made in China » a « Created in China » conduit a une prise de conscience croissante de l’importance de la creativite comme un vecteur de progres et de croissance economique.Nous definissons les caracteristiques fondamentales de Shanghai comme une ville creative, en essayant de montrer si Shanghai est fondee sur une forme de double voie. Nous precisons l’idiosyncrasie de la culture chinoise comme un avantage naturel pour la creativite et nous explorons le potentiel de la mise en œuvre d’une politique dite « nudge policy ».

Le paradoxe schumpeterien est une interpretation des neo-schumpeteriens qui considerent que la pensee de J.-A. Schumpeter se singularise par une contradiction sur la question de la relation entre la taille des entreprises et leurs capacites novatrices. Nous rejetons cette interpretation en montrant que l’œuvre revet une veritable unite theorique. Seul un « glissement » de point de vue apparait sur le plan methodologique, mais la aussi des nuances doivent etre apportees au regard des assertions neo-schumpeteriennes.Codes JEL : B10

Network is often considered as a support of knowledge creation. We consider that two main forms of networks can be identified in the economy: horizontal and vertical. We propose to compare these networks according to the question of knowledge creation. The aim of this article is then to demonstrate mathematically the hypothesis that a decentralized network is more efficient in terms of knowledge creation. This hypothesis supposes that interactions between firms promote collective learning and collective knowledge and increase performances. We propose to describe, in terms of mathematical metaphors, the two forms of network in order to compare afterwards their dynamical evolution. JEL Codes: D85, L2, O3

International audience; Defining knowledge-based network is not easy because of the polysemous meanings of this concept (Antonelli 1995; Kogut 2000). Indeed, we think that this kind of network requires more rupture, instability, and disequilibrium, that is dilemmas (Cohendet et al. 1999; Nonaka 1990). This dual need also corresponds to the two hemispheres of the brain. The left hemisphere is related to rationality, consciousness, and logical reasoning, while the right hemisphere is more concerned with creativity and imagination. In this article, we formalize the knowledge-based network using organizational mutations governed by non-deterministic dynamics and viable constraints. In our model, network is viewed as a locus where knowledge is continuously built, managed, combined, tested, and selected between all of the participants of the network. This continuous process of creation and shaping of knowledge is driven by problem-solving activities. Action and knowledge deeply interact within the network. The knowledge-based network must constantly create, maintain, and resolve dilemmas. In that, the network undergoes evolutions that it must manage by preserving a viable behavior as solution between many dilemmas. We want to express here the idea that, in this logic of viability, the network does not seek an optimal structure but tries rather to preserve coherence between differences. Our assumption is that a network evolution is viable if it checks a constraint (called viability constraint) related to the dilemmas.

Based on an organisational knowledge creation model, we propose a new lecture of schumpeterian conjecture. Taxonomy of the variety of innovative behaviours of SME is elabored by considering knowledge for innovate., En nous fondant sur un modèle de création de connaissance organisationnelle, nous proposons une lecture originale de la conjecture schumpéterienne. Une taxinomie de la variété des comportements innovants des PME, est ainsi élaborée en fonction des connaissances pour innover., Munier Francis. La conjecture schumpéterienne : revue de la littérature empirique et apport de l'économie de la connaissance. In: Revue d'économie industrielle, vol. 104, 4e trimestre 2003. pp. 71-84.

The aim of the article is to empirically analyse the main factors, which allow the emergence of consensus. Moreover, we raise the question of the nature of the codified process involved which seems to be too reducing to promote knowledge flows within the community and, therefore, to contribute to learning processes and better choices about the future. Our analysis relies on a prospective investigation based on a Delphi type study carried out by BETA in 1994.

The aim of the article is to explore different aspects concerning the distinction between the expert and the consultant. We analyse theoretically and empirically these distinctions in the framework of the knowledge-based economy in order to introduce the central concepts of epistemic community and community of practice. The question is to know to which community experts and consultant belongs. We also investigate the role that some actors coming from outside the firm play in reinforcing knowledge creation and codification processes in the firm.

L’objet de l’article est d’analyser la relation entre la densite scientifique de la region et les competences pour innover des entreprises. Cette etude permet d’apporter des elements empiriques au concept de "Learning Region". Nous proposons un modele econometrique, sur la base de donnees individuelles de l’industrie francaise, pour tester l’influence de la densite scientifique regionale sur la detention des competences des firmes.

The aim of this article is to demonstrate analytically the central hypothesis of the model of organizational knowledge creation developed by I. Nonaka (1990; 1994; 1995). This hypothesis supposes that interactions between individuals in a firm promote collective learning and increase innovative performances of the firm. We propose to describe, in terms of mathematical metaphors, different forms of an organizational structure, each describing innovative behavior, in order to compare their dynamical evolution. Either the organization authorizes interactions between the individuals, or the process of innovation is summarized in the individual behaviors in the form of a message. We show that the dynamics of evolution of these two forms of regulation is identical. In other words, we show that the dynamics of innovative behavior where agents interact is the same as the dynamic where the innovative performances of the firm are included in individual's contribution.

It is argued in this article that the main problem for the modern, globalised firm is not one primarily of the unequal distribution of information, but rather of the difficulty of mobilising and integrating fragmented forms of localised knowledge. In such a context, the role of new means of telecommunication and cooperative working is investigated. It is shown that networking favours a transparent mode of governance characterised by inter-linked actors and their continuous stimulation. Thus, the con ceptualisation of the globalised firm as a collection of competences offers a frame work for analysing governance mechanisms, involving the issue of incentives.

The interpretation of Schumpeter’s works (1935, 1939, 1974) leads to the formulation of two major assumptions. The first suggests that a positive relation between an innovation and the power of the monopoly prevails. The second supposes that big companies innovate more proportionally than small and medium-sized enterprises (SMEs) (the intensity of the research increases more than proportionally with size). This conjecture has been analysed in several empirical studies (Kamien and Schwartz, 1975, 1982; Baldwin and Scott, 1987; Scherer, 1992). These works brought answers, but they also show, as recalled by Le Bas (1991), that this question does not present either evident theoretical or empirical proof. According to Scherer (1992), an accepted result would be that big companies are more predisposed to innovate since they have greater means (financial, human, etc.), while the advantage of the small firm in the process of innovation is especially focused on the organizational level. This result led some authors to propose other research. Cohen (1995) notably suggests targeting their work to the concept of competence to study the explanatory factors of the innovating behaviour rather than to try to analyse a direct relation between size and innovation, as an important source of bias (Acs and Audretsch, 1990).

This article stresses the importance of competencies, specifically relational competencies, in the innovation process. Innovation output is not only produced by R&D but also often supported by networks and interfirm relations that differ according to the size of the firm. We perform an empirical analysis of the relationship between French industrial firms’ relational competencies and their sizes. Our results show that the size and the technological intensity of their sector are strongly correlated with relational competencies. We give also some statistical results concerning the relationship between tacit and codified procedures and external versus internal sources of the competencies.

Guanxi is a specific part of Chinese business environment. Since the openness of China, it seems that a contradiction appears between the constraints of corporate governance and the cultural and traditional behaviour in business. Most of west analyses consider that Guanxi is only a form of corruption and therefore it should be fight it out. The originality of our work is to frame these questions in the context of recent concepts such as communities of practice and epistemic communities. Based on these concepts, we consider that the firm can be analysed from a dual perspective: cognitive and organisational. The first one belongs to the guanxi logic and the second one to the corporate governance. According to these framework, we point out the fact that guanxi provides an innovative network in order to diffuse and enhance knowledge.

PURPOSE: The PAX6 gene was first described as a candidate for human aniridia. However, PAX6 expression is not restricted to the eye and it appears to be crucial for brain development. We studied PAX6 mutations in a large spectrum of patients who presented with aniridia phenotypes, Peters' anomaly, and anterior segment malformations associated or not with neurological anomalies. METHODS: Patients and related families were ophthalmologically phenotyped, and in some cases neurologically and endocrinologically examined. We screened the PAX6 gene by direct sequencing in three groups of patients: those affected by aniridia; those with diverse ocular manifestations; and those with Peters' anomaly. Two mutations were investigated by generating crystallographic representations of the amino acid changes. RESULTS: Three novel heterozygous mutations affecting three unrelated families were identified: the g.572T>C nucleotide change, located in exon 5, and corresponding to the Leucine 46 Proline amino-acid mutation (L46P); the g.655A>G nucleotide change, located in exon 6, and corresponding to the Serine 74 Glycine amino-acid mutation (S74G); and the nucleotide deletion 579delG del, located in exon 6, which induces a frameshift mutation leading to a stop codon (V48fsX53). The L46P mutation was identified in affected patients presenting bilateral microphthalmia, cataracts, and nystagmus. The S74G mutation was found in a large family that had congenital ocular abnormalities, diverse neurological manifestations, and variable cognitive impairments. The 579delG deletion (V48fsX53) caused in the affected members of the same family bilateral aniridia associated with congenital cataract, foveal hypolasia, and nystagmus. We also detected a novel intronic nucleotide change, IVS2+9G>A (very likely a mutation) in an apparently isolated patient affected by a complex ocular phenotype, characterized primarily by a bilateral microphthalmia. Whether this nucleotide change is indeed pathogenic remains to be demonstrated. Two previously known heterozygous mutations of the PAX6 gene sequence were also detected in patients affected by aniridia: a de novo previously known nucleotide change, g.972C>T (Q179X), in exon 8, leading to a stop codon and a heterozygous g.555C>A (C40X) recurrent nonsense mutation in exon 5. No mutations were found in patients with Peters' anomaly. CONCLUSIONS: We identified three mutations associated with aniridia phenotypes (Q179X, C40X, and V48fsX53). The three other mutations reported here cause non-aniridia ocular phenotypes associated in some cases with neurological anomalies. The IVS2+9G>A nucleotide change was detected in a patient with a microphthalmia phenotype. The L46P mutation was detected in a family with microphthalmia, cataract, and nystagmus. This mutation is located in the DNA-binding paired-domain and the crystallographic representations of this mutation show that this mutation may affect the helix-turn-helix motif, and as a consequence the DNA-binding properties of the resulting mutated protein. Ser74 is located in the PAX6 PD linker region, essential for DNA recognition and DNA binding, and the side chain of the Ser74 contributes to DNA recognition by the linker domain through direct contacts. Crystallographic representations show that the S74G mutation results in no side chain and therefore perturbs the DNA-binding properties of PAX6. This study highlights the severity and diversity of the consequences of PAX6 mutations that appeared to result from the complexity of the PAX6 gene structure, and the numerous possibilities for DNA binding. This study emphasizes the fact that neurodevelopmental abnormalities may be caused by PAX6 mutations. The neuro-developmental abnormalities caused by PAX6 mutations are probably still overlooked in the current clinical examinations performed throughout the world in patients affected by PAX6 mutations.

Axenfeld Rieger syndrome (ARS) is an autosomal dominant inherited disorder affecting development of the ocular anterior chamber, abdomen, teeth and facial structures. The PITX2 gene is a major gene encoding a major transcription factor associated with ARS.ARS patients were collected from six unrelated families. Patients and their families were ophthalmologically phenotyped and their blood was collected for DNA extraction. We screened the coding region of human PITX2 gene by direct sequencing. The consequences of the mutations described were investigated by generating crystallographic representations of the amino acid changes. In order to better understand the occurrence of glaucoma in ARS patients, we studied the PITX2 gene expression in human embryonic and fetal ocular tissue sections.We identified four novel PITX2 genetic alterations in four unrelated families with ARS. These mutations included two nonsense mutations (E55X and Y121X), an eight nucleotides insertion (1251 ins CGACTCCT) and a substitution (F58L), in familial and sporadic cases of ARS. We also showed for the first time that PITX2 is expressed at early stages of the human embryonic and fetal periocular mesenchyme, as well as at later stages of human development in the fetal ciliary body, ciliary processes, irido corneal angle and corneal endothelium. The human fetal eye PITX2 gene expression pattern reported here for the first time provides a strong basis for explaining the frequent occurrence of glaucoma in patients affected by PITX2 gene mutations.Two mutations identified affect the homeodomain (E55X and F58L). The E55X nonsense mutation is likely to alter dramatically the DNA-binding capabilities of the PITX2 homeodomain. Furthermore, there is a complete loss of the carboxy-terminal part of the PITX2 protein beyond the site of the mutation. The phenylalanine F58 is known to contribute to the hydrophobic network of the homeodomain. The crystallographic representations of the mutation F58L show that this mutation may change the conformation of the helical core. The F58L mutation is very likely to modify the homeodomain conformation and probably alters the DNA binding properties of PITX2. The other mutations (Y121X and the eight-nucleotide insertion (1251 ins CGA CTC CT) CGA CTC CT, at position 224 in PITX2A) result in partial loss of the C-terminal domain of PITX2. Pitx2 synergistically transactivates the prolactin promoter in the presence of the POU homeodomain protein Pit-1. Pitx2 activity is regulated by its own C-terminal tail. This region contains a highly conserved 14-amino-acid element involved in protein-protein interactions. The C-terminal 39-amino-acid tail represses DNA binding activity and is required for Pitx2 interactions with other transcription factors, for Pitx2-Pit-1 interaction and Pit-1synergism. Pit-1 interaction with the Pitx2 C terminus masks the inhibitory effect and promotes increased DNA binding activity. Thus, the partial or complete loss of the C terminus tail can lead to decreased or absent DNA binding activity and trigger severe ARS phenotypes. Our in situ hybridization results obtained on human embryonic and fetal ocular tissue sections constitute the first molecular histological data providing an explanation for the occurrence of precocious glaucoma in human patients affected by ARS caused by PITX2 mutations. Further structural and biochemical studies are needed for understanding the wide spectrum of clinical phenotypes caused by the increasing number of new PITX2 mutations found in ARS affected patients.

On the basis of the recent concepts of epistemic communities and communities of practice, we show that the firm can be defined according to a form of double duality: cognitive and organisational. The interest of this approach is to put ahead the differentiated behavior from the manager and the entrepreneur inside the firm. It also puts in light the important questions concerning the organisational tensions under the vision of the knowledge-based economies.

On the basis of the recent concepts of epistemic communities and communities of practice, we show that the firm can be defined according to a form of double duality: cognitive and organisational. The interest of this approach is to put ahead the differentiated behavior from the manager and the entrepreneur inside the firm. It also puts in light the important questions concerning the organisational tensions under the vision of the knowledge-based economies., En partant des concepts récents de communautés épistémiques et de communautés de pratique, nous montrons que l'entreprise peut être définie selon une forme de double dualité : cognitive et organisationnelle. L'intérêt de cette approche est de mettre en avant le comportement différencié du manager et de l'entrepreneur dans l'entreprise. Elle met également en perspective les questions importantes des tensions organisation-nelles sous l'angle de l'économie des connaissances., Créplet Frédéric, Dupouët Olivier, Kern Francis, Munier Francis. Dualité cognitive et organisationnelle de l'entreprise : le rôle différencié du manager et de l'entrepreneur. In: Revue d'économie industrielle, vol. 95, 2e trimestre 2001. pp. 9-22.

On the basis of the recent concepts of epistemic communities and communities of practice, we show that the firm can be defined according to a form of double duality: cognitive and organisational. The interest of this approach is to put ahead the differentiated behavior from the manager and the entrepreneur inside the firm. It also puts in light the important questions concerning the organisational tensions under the vision of the knowledge-based economies.

The schumpeterian paradox is an interpretation of the néo-schumpeterians which consider that the thought of J.A. Schumpeter is made conspicuous by a contradiction on the question of the relation between the size of the companies and their innovatives capacities. We reject this interpretation by showing a true theoretical unit. Only a "slip" from point of view appears on the methodological level, but nuances must also be brought.