ED Mathématiques et Informatique
RANKIN-SELBERG P-ADIC L-FUNCTIONS AT SEMISTABLE POINTS
by Martin FRANCQUEVILLE (IMB - Institut de Mathématiques de Bordeaux)
The defense will take place at 15h30 - Salle des conférence Institut de Mathématiques de Bordeaux Université de Bordeaux 351, cours de la Libération - F 33 405 TALENCE
in front of the jury composed of
- Denis BENOIS - Professeur - Université de Bordeaux - Directeur de these
- Kâzim BüYüKBODUK - Associate Professor - University College Dublin - Rapporteur
- Mladen DIMITROV - Professeur - Université de Lille - Rapporteur
- Filippo NUCCIO - Maître de conférences - Université Jean Monnet - Examinateur
We can associate a complex $L$-function to a couple of modular forms. To study this complex $L$-function, we can construct a $p$-adic $L$ function which interpolates the values of the complex $L$-function, up to a multiplicative factor. It can happen that this factor vanishes. in this case, the $p$-adic $L$ function vanishes, and we lose the information on the complex $L$-function's value : this is the trivial zero phenomenon. Conjecturally, it should be possible to recover the information on the complex $L$-function's value through the $p$-adic $L$-functions's cyclotomic derivative. In this thesis, we consider the case where one modular form is semistable, while the other one is cristalline. We give the interpolation formula between the complex $L$-function and the $p$-adic $L$-function, and we highlight the conditions needed for a trivial zero to appear. finally, we show a formula giving the $p$-adic $L$-function's cyclotomic derivative as a function of the $mathcal{L}$ invariant and the complex $L$-function.
ED Sciences de la Vie et de la Santé
Impact of immunosuppressive myeloid cells in the induction of cancer stem cells.
by Thomas BOYER (Immunologie Conceptuelle, Expérimentale et Translationnelle)
The defense will take place at 14h00 - Amphithéâtre BBS Bâtiment Bordeaux Biologie Santé (BBS) 2 Rue Dr Hoffmann Martinot, 33000 Bordeaux
in front of the jury composed of
- Charlotte DOMBLIDES - Maîtresse de conférences - praticienne hospitalière - Université de Bordeaux - Directeur de these
- Florent GINHOUX - Directeur de recherche - Institut Gustave Roussy - Rapporteur
- Julie PANNEQUIN - Directrice de recherche - Université de Montpellier - Rapporteur
- Maha AYYOUB - Professeure des universités - Université de Toulouse - Examinateur
- Macha NIKOLSKI - Directrice de recherche - Université de Bordeaux - Examinateur
- Fabrice LALLOUÉ - Professeur des universités - Université de Limoges - Examinateur
- Frédéric SALTEL - Directeur de recherche - Université de Bordeaux - Examinateur
The tumor microenvironment is strongly influenced by myeloid cells, with macrophages, neutrophils, and monocytes being major representatives. Research over the past decades has shown that almost all tumors are infiltrated in myeloid cells, making it impossible for “cold” tumors to exist with respect to these cells. Moreover, results from numerous clinical studies focusing on the myeloid immune compartment clearly show that these cells are almost universally associated with poor clinical outcome in patients, motivating a better understanding of their biology and efforts to target them. However, a central question has long been to understand what determines the functions of these cells in cancer. During emergency myelopoiesis, pathological activation of myeloid progenitors gives rise to myeloid-derived suppressor cells (MDSC), a term that encompasses a group of immature cells with a common property: immunosuppression. Indeed, MDSC play a crucial role in regulating antitumor immune responses but also promote tumor progression through non-immunological mechanisms, such as influencing angiogenesis and the extracellular matrix, resistance to therapies, and the preparation of the pre-metastatic niche. The preparation of the pre-metastatic niche is essential for the emergence of metastases at distant sites from the primary tumor, the leading cause of cancer-related deaths. These metastases are initiated by a subpopulation of tumor cells with stem-like properties: cancer stem cells (CSC). These cells, also known as Tumor-Initiating cells (TIC), encompass a minor subpopulation within the tumor and are characterized by intrinsic properties such as self-renewal potential, asymmetric division, and the ability to induce a new, heterogeneous tumor. Highly plastic, CSC transition from one cellules state to another through the epithelial-to-mesenchymal transition (EMT) or its counterpart, the mesenchymal-to-epithelial transition (MET). Therefore, a better understanding and specific treatment strategies targeting CSC could transform clinical management and significantly improve patient survival rates. The complexity of the tumor microenvironment, reflected by the presence of numerous actors and their interactions, exerts strong selective pressure on cancer cells and provides a favorable environment for the growth of CSC. Furthermore, the clinical implications associated with the issues of MDSC and CSC drive the emergence of studies on their reciprocal interactions, but the limitations in detecting these two actors make the evaluation and understanding of their interaction mechanisms diffuse and incomplete. In this thesis, we studied the role of suppressive myeloid cells in the induction of cancer cells with stemness properties. We have shown Human Monocyte Derived Suppressive Cells (HuMoSC) generated in vitro, but also their murine and patient derived equivalent promoted the apparition of CSC. Our results have highlighted a stemness induction mediated through a direct cell-to-cell contact and involving membrane-bound TGF-β. Finally, transcriptomic study of myeloid and cancer cells allowed us to identify a subpopulation of myeloid cells, expressing the glycoprotein CD52, as responsible for the immunosuppressive properties and the plasticity of CSC towards a mesenchymal-like phenotype.
The impact of proton pump inhibitors on immune checkpoint therapy efficacy
by Eloïse RAMEL (Immunologie Conceptuelle, Expérimentale et Translationnelle)
The defense will take place at 9h30 - Amphithéatre bâtiment BBS Bâtiment BBS 2 rue Dr Hoffman Martinot 33000 Bordeaux
in front of the jury composed of
- Thierry SCHAEVERBEKE - Professeur des universités - praticien hospitalier - Université de Bordeaux - Directeur de these
- Philippe LESNIK - Directeur de recherche - Umrs 1166-Ican – Unité de recherche sur les maladies cardiovasculaires et métaboliques - Rapporteur
- Laurence DELHAES - Professeur des universités - praticien hospitalier - Université de Bordeaux - Examinateur
- Benoit CHASSAING - Directeur de recherche - Institut Pasteur - Rapporteur
- Christel DEVAUD - Chargée de recherche - Centre de recherche en cancérologie de Toulouse - Examinateur
As immune checkpoint inhibitors (ICIs) revolutionize the management of metastatic cancers, several studies have highlighted the importance of the gut microbiota in response to these therapies (Routy et al., 2018; Matson et al., 2018; Gopalakrishnan et al., 2018). Microbial signatures are defined based on the response to ICIs; responders seem to have a microbiota rich in Lachnospiraceae, while non-responders show an enrichment in Streptococcaceae (McCulloch et al., 2021). While it is clear that antibiotics unfavorably alter the microbiota composition, thus affecting the efficacy of ICIs, other commonly used medications are also associated with dysbiosis in humans. These medications were assessed when administered concomitantly with the initiation of an ICI in a retrospective study conducted at the Bordeaux University Hospital on over 600 patients treated for advanced cancer. Negative associations were observed between prognostic criteria (survival, response rate, etc.) and certain co-medications, notably proton pump inhibitors (PPIs) (Kostine et al., 2021). PPIs are known to induce dysbiosis in humans (Jakson et al., 2016; Imhan et al., 2016), characterized by an increase in Streptococcus and Lactobacillus and a decrease in Lachnospiraceae, which can be restored upon discontinuation of the treatment (Nagata et al., 2022). This is likely due to the translocation of oral bacteria to the intestine following an increase in gastric pH. Given these observations, which do not establish a causal link, we chose to study the influence of PPIs on the response to ICIs using a murine model. We examined the direct effect of PPIs in vitro on tumor cells and immune cells (CD8+ T cells, NK cells, etc.). Concurrently, to study the microbiota, we used various murine cancer models with subcutaneous grafts (MCA205, MC38, RET) in mice treated or not with a PPI (omeprazole). The mice were then treated with an ICI (anti-PD-1/PD-L1 or anti-CTLA-4) and sacrificed to analyze tumors and spleens by flow cytometry and preserve the intestines for microbiota study (sequencing, qPCR, or culturomics). Our firsts results demonstrate omeprazole-induced dysbiosis in mice, particularly in the colon, though the microbial species characterizing this dysbiosis differ from those observed in humans. Omeprazole does not appear to directly influence the response to ICIs in mice. However, the oral colonization of microbial species from human saliva could be a key factor to reproduce clinical observations.
ED Sociétés, Politique, Santé Publique
Use and misuse of antibiotics among children under 5 years old at primary health centers in West and Central Africa
by Emelyne GRES (Bordeaux Population Health Research Center)
The defense will take place at 15h00 - Salle J.Mann (rez-de-chaussée de l'ISPED) - Université de Bordeaux, 146 Rue Léo Saignat, 33000 Bordeaux
in front of the jury composed of
- RENAUD BECQUET - Directeur de recherche - Bordeaux Population Health (Inserm, IRD, Université de Bordeaux) - Directeur de these
- Maryline BONNET - Directrice de recherche - IRD Montpellier - Rapporteur
- Tessa GOETGHEBUER - Directrice de recherche - Department of Paediatrics, CHU Saint-Pierre, Université libre de Bruxelles (ULB) - Rapporteur
- Valériane LEROY - Directrice de recherche - CERPOP, équipe SPHERE, INSERM, Université de Toulouse III Paul Sabatier - CoDirecteur de these
- Xavier ANGLARET - Directeur de recherche émérite - Bordeaux Population Health (Inserm, IRD, Université de Bordeaux) - Examinateur
- Koumavi Didier EKOUEVIE - Professeur assistant - Faculté des Sciences de la Santé, Université de Lomé, Togo - Examinateur
- Françoise RENAUD - Docteure - Organisation Mondiale de la Santé - Examinateur
- Carlo GIAQUINTO - Professeur des universités - Département de santé de la femme et de l'enfant de l'Université de Padoue - Rapporteur
In low- and middle-income countries, infectious diseases are the leading cause of infant mortality, making antibiotics a crucial pillar of medical care. However, the increasing use of these drugs often comes with inappropriate prescriptions due to the lack of trained personnel and reliable diagnostic resources. The World Health Organization (WHO) warns against the irrational use of antibiotics. Unnecessary exposure to these drugs increases the risk of serious adverse effects, raises healthcare costs, and contributes to the emergence of antibiotic resistance. Despite these issues, the absence of antibiotic prescription monitoring systems leads to a lack of data, particularly for the paediatric population, limiting the implementation of appropriate interventions. My doctoral work involved describing and quantifying the use and misuse of antibiotics in sick children under 5 years old in primary health centres (PHCs) in West and Central Africa. As part of the AIRE project, we analysed antibiotic prescription practices for 15,936 sick children under 5 years old consulting public PHCs in Burkina Faso, Guinea, Mali, and Niger between June 2021 and July 2022. The results show high rates of antibiotic prescription in children (2 months to 2 years), reaching 71% in Burkina Faso, 66% in Guinea, 63% in Mali, and 36% in Niger. In neonates, the proportions were equally high, reaching 83% in Burkina Faso. Most prescribed antibiotics belonged to the Access group (having a low risk of resistance development) of the WHO's AWaRe classification, in line with recommendations. Analysis of the adequacy of these prescriptions regarding the IMCI (Integrated Management of Childhood Illness) guidelines applied in PHCs of different countries indicates high rates of overprescription, defined by the prescription of antibiotics to children ineligible for antibiotic therapy according to IMCI recommendations. Among the 9,791 children aged 2 months to 2 years, 49% were not eligible for an antibiotic prescription, but more than 52% still received one. This overprescription was associated with young age, prescriptions during the dry season, respiratory symptoms, and a negative or unperformed malaria test. The randomized clinical trial conducted in the Democratic Republic of Congo, evaluating simplified management of acute malnutrition (OptiMA), also allowed us to study the prevalence of antibiotic use in a different context. During the trial follow-up, 17.8% of the 482 children with severe acute malnutrition received at least one antibiotic, with no significant difference between the standard and simplified management protocols. Finally, we conducted a systematic literature review to identify available antibiotic stewardship programs in paediatric contexts in low- or middle-income countries. This research highlights different interventions depending on the level of child care. Hospitals prioritize protocols and audits, while health centres focus on clinician training and the implementation of prescription aid tools (clinical guidelines or electronic algorithms). This work provides new insights into antibiotic prescription practices in children in Africa, highlighting issues related to inappropriate prescriptions. Solutions exist and are beginning to be implemented in several developing countries. These results aim to alert authorities to the magnitude of the problem and encourage the development of appropriate antibiotic stewardship programs.