ED Sciences Chimiques
Correlation between molecular dynamics, crystalline polymorphism and electroactive properties of poly(vinylidene fluoride)-based polymers for enhanced pyroelectric and energy-harvesting applications
by Joulia HOUSSEINI (Laboratoire de Chimie des Polymères Organiques)
The defense will take place at 9h00 - Amphi 2 ENSMAC 16 av. Pey Berland 33600 Pessac
in front of the jury composed of
- Georges HADZIIOANNOU - Professeur des universités - Université de Bordeaux - Directeur de these
- Guillaume FLEURY - Professeur des universités - Université de Bordeaux - CoDirecteur de these
- Sébastien ROLAND - Maître de conférences - Arts et Métiers ParisTech - Rapporteur
- Grégory STOCLET - Maître de conférences - Université de Lille - Rapporteur
- Philippe POULIN - Directeur de recherche - CNRS - Examinateur
- Guilhem RIVAL - Maître de conférences - INSA Lyon - Examinateur
Vinylidene Fluoride (VDF)-based polymers are well-known electroactive materials with their high output functional performance leveraged by the piezoelectric, pyroelectric, and electrocaloric effects. Besides, their outstanding electroactive properties, their ability to be incorporated into flexible devices allow them to be integrated into a broad range of applications such as sensors, energy storage, printed memories, electro caloric refrigeration, artificial muscles devices. The dielectric properties of VDF-based polymers are strongly influenced by their macromolecular architecture and semi-crystalline structure. Consequently, understanding the relationship between chemical sequence, crystallinity and electroactive properties is essential to optimize their performance and stability in targeted applications. Modulation of their electroactivity is directly associated with the development of crystalline polymorphism, which can be refined by variations in processing conditions. The central objective of this Ph.D. thesis is to further decipher the multiple semi-crystalline structures of VDF-based polymers and correlate crystalline polymorphism with electroactive behavior. In this work, we particularly delved into the integration of P(VDF-co-TrFE) copolymer into pyroelectric devices, by highlighting the impact of the casting and annealing processes on the semi-crystalline structure and the final pyroelectric properties. A combination of X-ray scattering, differential scanning calorimetry, dielectric spectroscopy and polarization cycles measurements were used to probe the structural characteristics of P(VDF-co-TrFE) layers as function of the film processing methods, leading to the optimization of the final pyroelectric response. Next, we sought at the optimization of P(VDF-ter-TrFE-ter-CTFE) systems used for energy-harvesting or cooling applications by rationalizing the impact of processing conditions – with a focus on the role of the casting solvents – on the relaxor ferroelectric properties. Finally, we have explored the use of solid state nuclear magnetic resonance spectroscopy to unravel the relationship between macromolecular structure, crystalline polymorphism and electroactive properties, which allows us to provide a clearer picture of these complex systems by differentiating three different states of ordering in these materials: an amorphous, rigid-amorphous and crystalline phases. In summary, this study aims to establish connections between the macromolecular architecture of electroactive polymers and their thin film crystalline structure to enhance their dielectric functionalities for specific applications.
ED Sciences de la Vie et de la Santé
Metabolic liver disease and hepatocellular carcinoma: prediction from carcinogenesis to treatment response through proteomic profiling
by Adèle DELAMARRE (BoRdeaux Institute of onCology)
The defense will take place at 14h00 - amphithéatre RDC du bâtiment BBS Bâtiment Bordeaux Biologie Santé 2, rue du Docteur Hoffman Martinot 33000 Bordeaux
in front of the jury composed of
- Victor DE LEDINGHEN - Professeur des universités - praticien hospitalier - BORDEAUX INSTITUTE OF ONCOLOGY (BRIC), UMR 1312 INSERM - Directeur de these
- Clotilde ALVES-GUERRA - Directrice de recherche - Institut Cochin - Rapporteur
- Jean-Marie PERON - Professeur des universités - praticien hospitalier - CHU de TOULOUSE, Service hépato-gastro-entérologie - Rapporteur
- Valérie PARADIS - Professeure des universités - praticienne hospitalière - Centre de recherche sur l'inflammation, UMR 1149 Inserm – Université Paris Cité – ERL CNRS 8252 - Examinateur
Metabolic dysfunction-associated steatohepatitis (MASH) is responsible for up to 35% of hepatocellular carcinomas (HCC) worldwide and is the leading cause of liver transplantation for HCC in the United States. Unlike other etiologies, a third of MASH-driven HCC develop in non-cirrhotic livers, thereby escaping screening recommendations restricted to cirrhotic patients, and leading to late diagnosis and poor prognosis. Systematic screening is not feasible due to the high number of patients, and there is currently no predictive marker for HCC development. Moreover, in case of advanced HCC, the only available treatments are palliative systemic therapies. After years of monotherapy with sorafenib, the combination of atezolizumab and bevacizumab, which includes immunotherapy and anti-angiogenic treatment, is now recommended as first-line treatment. However, the response rate remains restricted to 30%, few patients have access to second-line treatment, and there are no predictive factors of response. Tissue proteomic profiling by mass spectrometry is a comprehensive and unbiased approach adapted to these complex issues. It enabled our team to identify a predictive signature of non-response to atezolizumab/bevacizumab associated with a metabolic shift. During my PhD, my first aim was to identify a proteomic signature of prediction of MASH-driven HCC and to study pathways involved in carcinogenesis. The second aim was to validate in a 3D cellular model the implication of decreased oxidative metabolism in resistance to atezolizumab/bevacizumab. Firstly, we conducted a retrospective study on liver biopsies from 20 MASH patients: 11 patients who developed HCC within 15 years following their initial biopsy (group 1, with a median time from biopsy to HCC of 7.70 years) and 9 control patients (group 2). The patients were similar in clinical and histological terms. We obtained a proteomic signature of HCC prediction consisting in 330 significantly deregulated proteins, which allowed differentiation between the two groups. This proteomic signature was validated in a cohort of 13 new patients. Among these 330 proteins, prothymosin alpha (PTMA) was significantly overexpressed in group 1, with the highest ratio between the two groups. PTMA is overexpressed in many cancers including HCC and is involved in cell proliferation and apoptosis resistance pathways, making it a relevant candidate. Functional validation of PTMA is ongoing in a cellular model of MASH. Secondly, we developed a model of immune infiltration within an HCC spheroid and mimicked the metabolic shift of non-responder patients with a pharmacological inhibitor of mitochondrial respiratory chain. We demonstrated a decrease in immune infiltration in treated spheroids, which may contribute to the reduced efficacy of immunotherapy in these patients. Our proteomic signature yields promising results for predicting MASH-driven HCC, highlighting a potential early involvement of PTMA. Investigating the role of PTMA and other identified targets could open research avenues for preventing tumor development. External validation of this signature in a larger cohort will be necessary before clinical application, in order to optimize HCC screening in MASH patients. The second part of this thesis identifies a mechanism of HCC resistance to atezolizumab/bevacizumab. This approach could be extended to all first-line treatments of HCC, paving the way for personalized medicine and future research to enhance treatment efficacy.
ED Sociétés, Politique, Santé Publique
Patterns of Adverse Drug Reactions in Patients with Drug-Resistant Tuberculosis in Eswatini and comparison of AE Reports characteristics with a worldwide database: A Prospective and Retrospective Studies
by Alemayehu DUGA (Bordeaux Population Health Research Center)
The defense will take place at 11h00 - Virtual Akaki Kaliti Sub City, Addis Ababa, Ethiopia
in front of the jury composed of
- Albert FIGUERAS - Professor - Professor, World Health Organisation - CoDirecteur de these
- Sandile KHAMANGA - Professeure des universités - Rhodes University, Republic of South Africa - Rapporteur
- Jean Marie HABARUGIRA - Cadre scientifique - European Commission DG RTD. GH EDCTP3 JU - Examinateur
- Francesco SALVO - Professeur des universités - Université de Bordeaux, France - Directeur de these
- Mónica Tarapues ROMáN - Docteure - Uppsala Monitoring Center (Uppsala, Sweden) - Examinateur
- Annalisa CAPUANO - Professeur des universités - Università Napoli, Luigi Vanvitelli. - Rapporteur
Drug-resistant tuberculosis (DR-TB) is a significant public health concern, particularly in developing countries like Eswatini. The treatment of DR-TB requires the combination of several medicines over several months, which can lead to adverse drug reactions (ADRs). This thesis aims to characterize and describe a comprehensive analysis of the safety profiles of DR-TB medicines used in treating DR-TB at global and national levels. Firstly, we evaluated the magnitude and characteristics of DR-TB-related ADRs by analyzing reports from the World Health Organization (WHO) database (VigiBase). We then investigated the patterns of ADRs in patients with DR-TB in all treatment sites in the Kingdom of Eswatini. Finally, we analyzed ADRs associated with the use of clofazimine (CFZ) and linezolid (LZD) in a prospective cohort study at one of the regions in Eswatini. The analysis of individual case safety reports (ICSR) from VigiBase revealed that pyrazinamide was the most reported medicine associated with ADRs, followed by ethionamide and cycloserine. The study found that almost half of the reports required complete withdrawal of the suspected medicine(s), which significantly impacts treatment adherence and ultimately leads to drug resistance. The study underlines the urgent need to remain alert for potential ADRs throughout treatment, emphasizing the immediate action required to prevent treatment failure. The retrospective cohort study provides crucial insights into the patterns of ADRs in 670 patients with DR-TB in Eswatini. The results reveal that 44% of patients experienced at least one ADR, with bedaquiline being associated with the highest number of ADRs. The study also identified age as a significant factor in the occurrence of peripheral neuropathy and arthralgia-related ADRs. These findings underscore the need for enhanced safety monitoring of patients undergoing DR-TB treatment to ensure prompt and appropriate ADR management, thereby reducing the risk of treatment failure. The findings of the prospective cohort study indicate that 80% of patients treated with CFZ or LZD experienced adverse drug reactions (ADRs). CFZ was associated mainly with mild ADRs, whereas LZD was linked to more severe ADRs, such as anemia, peripheral neuropathy, and optic neuritis. These findings underscore the importance of closely monitoring ADRs linked to these repurposed medicines throughout the treatment duration. This thesis significantly contributes to understanding DR-TB medicines' safety profiles in various contexts. The studies underscore the critical importance of closely monitoring ADRs linked to these medicines throughout the treatment duration to ensure patient safety and positive treatment outcomes. Adverse drug reactions, whether they are directly related to medicines or not, might lead to low treatment adherence and discontinuation. Such outcomes can further compromise the effectiveness of the treatment regimen, leading to incomplete eradication of the bacteria and drug resistance. Therefore, it is of utmost importance to monitor the safety of DR-TB medicines to ensure ADR management, thus lowering the chance of treatment failure. Understanding the impact of ADRs and taking proactive measures to address them will significantly contribute to more favorable treatment outcomes and facilitate the comprehensive eradication of DR-TB, a global health priority. Keywords: pharmacovigilance, public health, Drug-Resistant Tuberculosis, Medicine safety, adverse drug reaction, safety surveillance Title: Drug-Resistant Tuberculosis Medicines Safety Profile: A Perspective from Eswatini and WHO Vigibase® Global Data