Estimation of survival is used in many medical studies that aimed to estimate the prognostic of patient, the impact of some variables on the disease under study. More generally, estimation of survival is a valuable indicator of progress in disease control. For chronic diseases, more especially for cancer, the creation of registries has permitted to increase the knowledge in the epidemiology of the diseases under study. Over the past decade, population-based cancer registry data have been used increasingly worldwide to evaluate and improve the quality of cancer care. In this context, analyses are generally performed using methods of estimation of excess mortality that aimed at estimating and modelling the excess mortality to which a studied group of patient’s cancer is subjected and at estimating their net survival (i.e. the survival corrected for all the other causes of death). In this context, the objective of the modelling is to estimate the impact of prognostic factors on the excess mortality risk and to assess the cure rate in different subgroups of patients. Estimation of the survival of cancer’s patients, obtained from population-based data collected by cancer registries, are analysed regularly and published by the different European countries. Comparisons between countries are justified only if the methods used for that have taken into account bias relative of observational studies and if they are the result of a thought and a strategy adopted by all the partners. The development and the homogenisation of such methodology are totally justified in this context. The overall aim of this project is to improve the current methods for estimating net survival and to broaden their field of application in order to obtain i) tools to model complex data, and ii) more accurate estimates that enable to have information on survival for a studied disease and on its public health impact. More precisely, there are three main research axes devoted to: (1) propose new methodological developments to answer questions that are the result of our works during our previous project (MESURE); (2) extend and assess new statistical methods; (3) transfer net survival methods used in cancer to some other specific applications. These themes correspond to some of the actual challenges in the estimation of net survival. Following our previous project, CENSUR project is more ambitious, considering the scope of the methods investigated and the new development that are envisaged. While the focus is on methodological aspects, the network implies also members that have skills in epidemiology and in population-based data analyzes with the objective to produce survival statistics useful in Public Health. This project will allow to reinforce a network including 5 French team, 3 European and 1 Canadian, having complementarities, internationally known, and having experience in the framework of excess mortality and the development of statistical methods. At the end of this project, in order to optimize the use of methods to estimate net survival, we will organize a course. Furthermore, free-licensed statistical programs derived from our work will be available for the scientific community. If the project goes on well, it will allow to propose an adapted methodology in order to obtain correct estimates of the excess mortality for a disease under study and to its determinants. This methodological approach is a preliminary condition for a rational management of disease, on its medical and socio-economic aspects, that will be obtained from registries data, clinical data, or enterprise data.

Azole resistance in Aspergillus is one of the emerging public health concerns, listed as a WHO priority and suited to an integrated One Health approach. Selective pressure due to the use of azole pesticides in agriculture being incriminated, identification of clinical and environmental resistance patterns, and a greater understanding of the factors driving this resistance are urgently needed in order to issue recommendations to the stakeholders. The multidisciplinary AspergillusOne-health project strengthened with model and innovative methodologies (WGS, genotyping, MALDI typing, metabarcoding, AI) aims to identify hotspots as possible sources for selection of azole-resistance in the environment, after the detection of azole-resistant Aspergillus in patients and patiens's home, avian facilities, the environment (farming and sawmills), and detection of the azole fungicides in soil and air. The role of resistance trait on Aspergillus fitness cost will be investigated, using environmental strains and mutants selected after fungicide pressure, to assess its clinical involvement.

The present program is based on 2 closely related discoveries that we have made recently: i) the diuretic, NKCC1 chloride importer antagonist, Bumetanide, that shifts the polarity of GABA from excitation to inhibition, decreases the severity of autism in children (Lemonnier et al., Transl Psych, 2012); ii) the oxytocin-mediated neuro-protective GABA excitatory-inhibitory shift that takes place during delivery is abolished in the valproate and fragile X rodent models of autism leading to persistent excitatory GABA, enhanced glutamatergic activity and gamma oscillations (Tyzio et al., Science, 2014). Pretreatment with bumetanide to the mother during the delivery period restores in offsprings physiological levels of chloride and attenuates the electrophysiological and behavioral autistic phenotypes (Tyzio et al., Science, 2014). Furthermore, blocking during the delivery period oxytocin signaling in naïve mothers produced autistic manifestations in off springs. These observations both confirm that intracellular chloride levels are elevated in autism and validate the potential use of Bumetanide as a treatment. In addition, our results, to the best of our knowledge, are the first ones that link an electrical event during delivery, a transmitter gated signal and a psychiatric disorder. Our current proposal is aimed at substantiating and generalizing our recent results suggesting important links between delivery, the polarity of GABA actions and autism. Our objectives are to determine if the deficient chloride regulation is a general feature of autism independently of the mutation by testing these alterations in other genetic models of autism and Tuberous Sclerosis. We shall also test if paravalbumin GABAergic interneurons (PV), that modulate the effects of oxytocin on brain networks, are altered early in autism, exciting their targets and affecting behaviorally relevant gamma oscillations. In addition, we will determine the mechanisms underlying the incidence of epilepsies in autism and the role of excitatory GABA. Finally, we shall examine if the administration of bumetanide outside the delivery period attenuates the pathogenesis of autism. This is important in order to better understand the priming role of the delivery process. The present program is highly innovative considering the complete lack of data on electrical activity of immature neurons in autism, the importance of developmental processes and our success in the therapeutic use of bumetanide to treat the disorder. This has considerable public health implications considering the links between complications during delivery, oxytocin and autism. The demonstration of common features between delivery, GABA signals, oxytocin, and various types of autism will impact heavily the research and treatment in autism and other developmental disorders. We do not anticipate an obstacle in performing the proposed project, as the techniques, preparations and animal models are available in the teams and their laboratories.

Mecp2-pathies represent an emerging field among severe X-linked mental retardation syndromes. Rett Syndrome (RTT) represents the prototype of these pathologies and accounts for 10% of the cases of profound intellectual disability in females. The causative gene is the methyl CpG-binding protein 2 (MECP2) gene, encoding a multifunctional protein thought to "modulate" the expression of genes by several independent mechanisms. In addition to Rett syndrome, we now know that there are twice more patients (men and women) with a mutation in the MECP2 gene causing a neurological disease of varying severity. Globally, MECP2 mutations are affecting 30,000 new patients each year worldwide. Given that almost all of these cases are sporadic, genetic counselling and prenatal diagnosis are not possible and the prevalence of these diseases will not change. To date, no treatments are available in Mecp2-pathies. Recently, we made an important discovery demonstrating that axonal transport is altered in the absence of Mecp2. The brain derived neurotrophic factor (Bdnf) gene is one of Mecp2 targets. We found that the expression of several genes involved in Bdnf trafficking, such as huntingtin (Htt) and huntingtin-associated protein (Hap1), is reduced in the brain of adult Mecp2-deficient mouse. We showed that the velocity of Bdnf containing vesicles of Mecp2-deficient neurons is reduced and that re-expression of Mecp2 in these cells rescues this phenotype. The present project aims to further investigate the mechanisms leading to a neuronal trafficking impairment in Mecp2-deficient neurons and to identify potential pharmacological therapies to counterbalance such defects. Neuronal trafficking is not only dependent on the quantity of the molecular motors and associated proteins (dynein, dynactin, Htt, Hap1), but it also requires the proper function of several kinases. Akt pathway has been described by partner 2 to directly phosporylate Htt, leading to the stimulation of a dynamic neuronal trafficking pathway. Recently, it was shown that the phosporylation of Akt at serine 473 was decreased in the cortex of Mecp2-deficient mice. Therefore we will determine if the main partners of the Akt-pathway are affected in Mecp2 deficiencies, with a particular emphasis on Htt (a direct Akt-downstream target). We will also evaluate the direct impact of pharmacological interventions (FK506) able to maintain the level of Htt phosphorylation in Mecp2-deficient mice. The Akt pathway is also strongly dependent on the activation of insulin/IGF1 receptors. IGF1 is downregulated in the brain of Mecp2-deficient mouse. We will now evaluate wether the pharmacological stimulation of insulin/IGF1 receptors can alleviate the possible defects of the Akt signaling pathway, in vitro (cell cultures) and in vivo (mouse model). Our previous results showed that not only Htt and Hap1, but also other molecular motors, were drastically affected in neurons lacking Mecp2. Interestingly, these factors are involved in the vesicular Bdnf transport throughout the axon and also in the transport of mitochondria. Therefore, we will evaluate the possibility that part of the RTT phenotype is due to alterations of the mitochondrial transport, cell metabolism and energy supply, especially in neurons. The Mecp2 protein is located in the cell nucleus and is known as a master transcriptional regulator while molecular motors are located in the cytoplasm. In our previous results we proposed that Mecp2 dosage could alter the neuronal trafficking through transcriptional deregulation. We will further investigate this hypothesis as well as evaluate the alternative hypothesis that Mecp2 could act directly at the cytoplasmic level by a novel, still unsuspected mechanism. Altogether our aim is to improve the understanding of Mecp2-pathies, allowing us to devise and test new pharmacological therapies in pre-clinical animal models that will eventually be used to improve the clinical outcome of the patients.