ED Droit
The contribution of scientific evidence to the manifestation of truth in arsenic poisoning cases (1808 to 1961)
by Alyssia FAVRE-PETIT-MERMET (INSTITUT DE RECHERCHE MONTESQUIEU)
The defense will take place at 9h30 - Salle des thèses, Bâtiment C, Université de Bordeaux, 16 avenue Léon Duguit, 33600 Pessac
in front of the jury composed of
- Laetitia GUERLAIN - Professeure - Université de Bordeaux - Directeur de these
- Marc ORTOLANI - Professeur - Université Côte-d'Azur - Rapporteur
- Mathieu SOULA - Professeur - Université Paris Nanterre - Rapporteur
- Christophe LASTÉCOUÈRES - Professeur - Université Bordeaux Montaigne - CoDirecteur de these
- Karen FIORENTINO - Professeure - Université de Bourgogne - Examinateur
- Yann DELBREL - Professeur des universités - Université de Bordeaux - Examinateur
In the nineteenth century, arsenic emerged as the poison par excellence : discreet, accessible, and long undetectable, it fueled some of the most notorious criminal cases and put the criminal justice system to the test. Faced with these invisible crimes, science was called upon to restore the truth. The rise of forensic medicine and toxicology, driven in particular by the work of Orfila, profoundly transformed poisoning trials. The scientific expert became a central figure, while analytical methods promised to objectify evidence. Yet, behind this apparent revolution, certainties began to waver. Techniques remained fragile, results were debated, and interpretations were sometimes contested. Through an examination of arsenic poisoning cases between 1808 and 1961, this thesis highlights the limits and ambiguities of scientific evidence. Far from imposing an unquestionable truth, such evidence operates within a space of uncertainty where scientific knowledge, judicial practices, and judges' convictions intersect. Judicial truth thus never fully coincides with scientific truth. Between the promise of certainty and the reality of doubt, toxicological evidence reveals the full complexity of the relationship between science and justice.
ED Sciences de la Vie et de la Santé
Characterization and targeting of cancer stem cells in gastric cancer: towards new diagnostic and therapeutic avenues
by Anissa ZAAFOUR (BoRdeaux Institute of onCology)
The defense will take place at 13h15 - Amphithéâtre RDC 2 rue du Docteur Hoffmann Martinot Bâtiment Bordeaux Biologie Santé 33000 Bordeaux
in front of the jury composed of
- Christine VARON - Professeure des universités - Université de Bordeaux - Directeur de these
- Florence RENAUD - Maîtresse de conférences - praticienne hospitalière - Faculté de Santé, Sorbonne Université, Centre de Recherche Saint Antoine - Examinateur
- Isabelle SAGOT - Directrice de recherche - Institut de Biochimie et Génétique Cellulaires UMR 5095 - Examinateur
- David SANTAMARIA - Directeur de recherche - Centro de Investigación del Cáncer - Rapporteur
- Barbara BESSETTE - Professeure des universités - OMEGAHEALTH : UMR INSERM 1308 CAPTUR Institut de recherche OMEGAHEALTH - Rapporteur
Cancer stem cells (CSC) represent a highly plastic subpopulation of cells capable of self-renewal, differentiation, initiating tumor growth, invading the bloodstream, and colonizing distant organs from the primary tumor. Resistant to conventional treatments, CSC can remain dormant, a quiescent state, in which cells survive with very little growth. They are thus undetectable by imaging for months or even years before triggering local or metastatic recurrence. CSC maintain their properties by hijacking signaling pathways. Enzymes such as proprotein convertases (PC) play a key role in the maturation of effectors in these pathways such as growth factors, integrins, and receptors. Despite the magnitude of this problem, the dissemination kinetics and dormancy mechanisms of CSC remain poorly studied and largely unknown in gastric adenocarcinoma (GC). Even with early diagnosis, the risk of GC recurrence is approximately 30% following surgical resection, with a peak occurring within 3 years of the operation. Furthermore, disseminated tumor cells (DTC) are detected in the bone marrow (BM) of non-metastatic patients at the time of surgery, with the majority subsequently developing hepatic rather than bone recurrence. This indicates that dormant cancer cells disseminate early to niches such as the BM and can reactivate years later. It is therefore crucial to understand the dissemination kinetics and dormancy of CSC in GC. In this context, the objectives were to: 1) Model GC dissemination and dormancy: We developed a sophisticated new triple-transgenic mouse model of gastric carcinogenesis induced by Helicobacter felis infection, in order to track the early dissemination of pre-CSC to various organs. This model reproduces the pre-neoplastic intestinal metaplasia observed in H. pylori-infected patients who develop GC, humanizing the model and accelerating carcinogenesis. Expression of the tdTomato tracer in the gastric mucosa enables detection of distantly disseminated cells. This model confirmed the very early dissemination of gastric cells to the BM and the liver during carcinogenesis. It will subsequently enable the characterization of DTC and their niches and serve as a preclinical model to test potential treatments. In vitro modeling of the BM was achieved by co-culturing BM-derived mesenchymal stem cells and GC cell lines under hypoxia, inducing a dormancy characterized by low proliferation and reversible G0 cell cycle arrest, while increasing the tumorigenic properties of the dormant cells. The molecular mechanisms governing CSC dormancy in GC remain to be explored using the established models. 2) Develop a therapeutic strategy to control residual disease: The combination of All-trans-retinoic acid and 5-Aza-2'-deoxycytidine (A/A) was tested to induce therapeutic dormancy in GC CSC. The treatment led to a reversible G0 arrest without inducing senescence or cell death, suggesting therapeutic potential for controlling disease progression and delaying recurrence in vivo. 3) Evaluate the impact of PC targeting as an anti-CSC therapeutic strategy in GC: Inhibition of PC activity using the general inhibitor decanoyl-RVKR-chloromethyl-ketone reduced tumor organoid formation, the drug efflux responsible for chemoresistance, the mesenchymal phenotype, and the invasive properties of CSC. These effects were accompanied by a repression of the YAP/TAZ/TEAD pathway in vitro. In vivo, PC inhibition reduced metastatic spread. Molecular analysis of patient tumors confirmed the predictive value of certain PC in GC, where high expression is associated with a poor prognosis.
Characterization of the subthalamo-cortical pathway and its involvement in the pathophysiology of Parkinson's disease
by Elba MOLPECERES SIERRA (Institut des Maladies Neurodégénératives)
The defense will take place at 13h00 - Amphithéâtre Centre Broca 146 Rue Léo Saignat, 33000 Bordeaux
in front of the jury composed of
- Véronique COIZET - Directrice de recherche - Institut des Neurosciences de Grenoble - Rapporteur
- Yasin TEMEL - Professeur - Maastricht University - Rapporteur
- Sandrine BERTRAND - Directrice de recherche - INCIA - Examinateur
- Daniel VOISIN - Professeur - Neurocentre Magendie - Examinateur
Parkinson's Disease (PD) is the second most common neurodegenerative disorder, present in 1-3% of the world's population over 60 years of age. PD is first characterized by the manifestation of motor symptoms, including rest tremor, akinesia/bradykinesia, muscle rigidity, postural instability, dystonia and postural/gait difficulties. In addition, PD also courses with non-motor symptoms, with some of them usually precede the onset of clinical motor signs, such as anxiety, depression, as well as cognitive, autonomic and sensory disorders. Pain represents a prevalent non-motor symptom of PD, affecting up to 80% of patients, yet remains inadequately characterized despite its high prevalence and heterogeneous clinical presentation. PD is characterized by the progressive death of dopaminergic neurons in the pars compacta of substantia nigra (SNc), which results in a disorganization of the neuronal activity of basal ganglia circuitry. The subthalamic nucleus (STN) is a small diencephalic structure playing a crucial role in these basal ganglia circuit by influencing output structures of the system and cortical areas, as its neurons project directly to the cortex. The STN is known to be involved in both motor and nociceptive functions, as well as in the pathophysiology of PD. In PD patients and parkinsonian animal models, such as MPTP monkeys or 6-OHDA rodents, significant changes in STN neuronal firing activity have been reported. Electrophysiological studies in parkinsonian condition show an increase in the firing rate and the proportion of bursty neurons, as compared to the regular firing pattern recorded in the STN in the control situation. In addition, there is an increase in the number of cells that show oscillatory activity. According to the anatomo-functional organization of the cortico-basal ganglia-thalamo-cortical model, hyperactivity in the STN would lead to an increased activity of the basal ganglia output structures and disorganization of the system. However, the STN exhibits direct projections to multiple cortical targets, including the primary motor cortex, and the specific functional contribution of these subthalamocortical pathways to parkinsonian symptoms remains to be elucidated. The thesis project aimed to investigate the anatomo-functional organization of direct STN-M1 cortical pathway in both normal and parkinsonian conditions, using a combination of chemogenetic and optogenetic approaches alongside with behavioral studies and in vivo electrophysiology in the transgenic Vglut2-cre mice. Our first results, show that selective chemogenetic inhibition of STN glutamatergic neurons significantly improved motor deficits and nociceptive abnormalities in a 6-OHDA mice model of PD. Anatomical tract-tracing studies demonstrate that STN neurons project to diverse cortical areas, with the majority of terminals localized in motor and somatosensory cortices. At the cellular level, STN glutamatergic neurons exhibit preferential synaptic connectivity with M1 interneurons relative to pyramidal cells. Finally, using optogenetic interrogation of the STN-M1 pathway we have demonstrated that selective inhibition of these projections attenuates motor and pain phenotypes in parkinsonian mice. Complementary in vivo electrophysiological recordings in anesthetized mice have shown that M1 neurons encode nociceptive information, and that PD-associated disruptions in their response properties are restored by optogenetic silencing of STN-M1 inputs. These results reveal for the first time the importance of the STN-M1 pathway in the pathophysiology of PD and its potential therapeutic implications.