During the last decade, substantial advances have been made in the understanding of the complex molecular, immunological and cellular disturbances involved in the initiation as well as evolution of myelodysplastic syndromes (MDS). In 85% of the mainly frail and older patient population, anemia is present at the time of diagnosis and is thus a major therapeutic challenge. High rates of primary resistance to erythropoiesis-stimulating agents (ESAs), the currently only approved standard therapy to treat anemia in lower-risk MDS, demand the development of novel and effcient drugs with a good safety profile. Luspatercept, a ligand trap of activin receptor II, is able to promote late stage erythropoiesis even in patients failing prior ESA treatment. The presence of ring sideroblastic phenotype defines a subgroup of patients with higher response rates. Additionally, recent developments in clinical research using HIF-1 or telomerase modulation by roxadustat or imetelstat are promising. Other areas of translational research involve targeting the inflammasome by anti-inflammatory drugs in order to improve anemia. These efforts will hopefully pave the way for new targeted treatment options for anemic low-risk MDS patients.

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Clostridium difficile, the causative agent of C. difficile infection (CDI), causes hundreds of thousands of hospital-acquired infections in the United States and Canada annually. Furthermore, the prevalence and severity of CDI has been on the rise in developed countries, especially with the appearance of “hypervirulent” strains. Detection of CDI is thus of great importance. Traditional detection methods can be time consuming or lack the desired sensitivity. On the other hand, aptamers pose great prospects as diagnostic and therapeutic agents. Aptamers are nucleic acid ligands with molecular recognition capabilities rivaling those of antibodies. They are obtained by a process of in vitro selection known as systematic evolution of ligands by exponential enrichment (SELEX). However, the current approach may result in aptamers that experience non-specific binding in complex or biological samples. Here, we propose a multiple domain selection (MDS) method for aptamer isolation. This method utilizes independent selections on separate components of a single target in order to obtain uniquely specific aptamers. The aptamers can then be unified into a heterobivalent construct able to recognize two sites on one target. We hypothesize the combined aptamer would result in greater affinity and specificity for the target, resulting in greatly increased aptamer utility in current and future applications. In the current study, we have cloned and purified full length C. difficile DnaK as well as the N-terminal domain (NTD) and C-terminal domain (CTD) of the protein. MDS was performed on each target and the resulting aptamers were combined into a heterobivalent construct. The construct resulted in an approximately 100-fold affinity increase relative to the single aptamer for DnaK, and could detect much smaller quantities of target. Although it experienced low level recognition of high concentrations of purified E. coli DnaK, there was no detectable non-specific binding in several biological samples. / Thesis / Master of Science (MSc)

Myelodysplastic syndromes (MDS) encompass a heterogeneous group of age-related hematopoietic disorders characterized by ineffective and incomplete hematopoiesis leading to an increased risk of acute myeloid leukemia (AML). The development of accurate and easily used in vitro models is crucial for understanding the pathogenesis of MDS and identifying potential therapeutic targets. Induced pluripotent stem cells (iPSCs) can be used to study MDS due to their ability to differentiate into any cell type depending on the environment. The main limitation is that the blood progenitors produced by iPSCs are of a fetal state, which hinders modeling of MDS, a disease of older adulthood. This study aimed to optimize the maturation state of blood progenitors derived from iPSCs by induction of the micro-RNA let-7, which, we hypothesize will increase the maturation and adult phenotypic state of hematopoietic progenitors. iPSC lines were generated from healthy controls and samples containing the SRSF2 mutation, a common mutation in MDS, containing a doxycycline-inducible, stabilized let-7 transgene. A stepwise differentiation efficiently drove the iPSCs toward hematopoietic progenitors and, subsequently, other mature lineages. The hematopoietic progenitors were characterized by assessing the expression of specific cell surface markers and functional properties using flow cytometry, colony-forming assays, and multi-lineage differentiation abilities. These findings demonstrate the potential of using iPSC engineering to create a novel model for MDS and other age-biased disorders by inducing let-7 expression in iPSCs and, when differentiating them, exposing them to doxycycline to promote an adult cell phenotype. This approach offers a valuable potential tool for elucidating the molecular mechanisms underlying these disorders and exploring potential therapeutic interventions. / 2026-03-13T00:00:00Z

No / Introduction Older people in care homes are at increased risk of medication errors and adverse drug events. The effect of formulation on administration errors is not known, that is whether the medicine is a tablet or capsule, liquid or device such as an inhaler. Also, the impact on administration errors of monitored dosage systems (MDS), commonly used in UK care homes to dispense tablets and capsules, is not known. This study investigated the influence of formulation and MDS on administration errors. Methods Administration errors were identified by pharmacists (using validated definitions) observing two drug rounds of residents randomly selected from a purposive sample of UK nursing and residential homes. Errors were classified and analysed by formulation and medicine delivery system. Results The odds of administration errors by formulation, when compared with tablets and capsules in MDS, were: liquids 4.31 (95% CI 2.02 to 9.21; p=0.0002); topicals/transdermals/injections 19.61 (95% CI 6.90 to 55.73; p<0.0001); inhalers 33.58 (95% CI 12.51 to 90.19; p<0.0001). The odds of administration errors for tablets and capsules not in MDS were double those that were dispensed in MDS (adjusted OR 2.14, 95% CI 1.02 to 4.51; p=0.04). Conclusions Inhalers and liquid medicines were associated with significantly increased odds of administration errors. Training of staff in safe administration of these formulations needs implementing. Although there was some evidence that MDS reduced the odds of an administration error, the use of MDS impacts on other aspects of medicines management. Because of this, and as the primary topic of our study was not MDS, a prospective trial specifically designed to evaluate the overall impact of MDS on medicine management in care homes is needed.

L’action humaine dans une séquence vidéo peut être considérée comme un volume spatio- temporel induit par la concaténation de silhouettes dans le temps. Nous présentons une approche spatio-temporelle pour la reconnaissance d’actions humaines qui exploite des caractéristiques globales générées par la technique de réduction de dimensionnalité MDS et un découpage en sous-blocs afin de modéliser la dynamique des actions. L’objectif est de fournir une méthode à la fois simple, peu dispendieuse et robuste permettant la reconnaissance d’actions simples. Le procédé est rapide, ne nécessite aucun alignement de vidéo, et est applicable à de nombreux scénarios. En outre, nous démontrons la robustesse de notre méthode face aux occultations partielles, aux déformations de formes, aux changements d’échelle et d’angles de vue, aux irrégularités dans l’exécution d’une action, et à une faible résolution. / Human action in a video sequence can be seen as a space-time volume induced by the concatenation of silhouettes in time. We present a space-time approach for human action recognition, which exploits global characteristics generated by the technique of dimensionality reduction MDS and a cube division into sub-blocks to model the dynamics of the actions. The objective is to provide a method that is simple, inexpensive and robust allowing simple action recognition. The process is fast, does not require video alignment, and is applicable in many scenarios. Moreover, we demonstrate the robustness of our method to partial occlusion, deformation of shapes, significant changes in scale and viewpoint, irregularities in the performance of an action, and low-quality video.

La littératie en santé (LS) désigne les connaissances, la motivation et les compétences permettant d’accéder, comprendre, évaluer et appliquer l’information dans le domaine de la santé. C’est un déterminant majeur de santé qui est fréquemment considéré comme un mécanisme des inégalités sociales de santé. Ce travail de thèse a comme objectif fondamental d’évaluer l’association entre la LS, les inégalités d’information et l’état de santé des personnes atteintes de cancers. Toutefois, devant le manque d’instruments de mesure de la LS, nos premiers travaux ont consisté en la validation d’outils de mesure en France. Nos travaux empiriques se sont appuyés sur les analyses de trois enquêtes.Ces analyses ont permis d’obtenir des éléments de validation de plusieurs échelles subjectives en version française évaluant la LS, la numératie et la décision partagée.Un niveau limité de LS a été montré associé à une moindre participation au processus de décision partagée, des comportements de recherche d’information et un état de santé mentale et physique altéré. De plus, les patients avec un niveau limité de LS sollicitent davantage le médecin généraliste et les services sociaux.La prise en compte du niveau de LS des patients pendant tout le parcours de soins nous parait indispensable. Cela pourrait permettre d’adapter l’information au niveau de LS afin de réduire les inégalités d’information et augmenter la participation des patients à la prise de décision. En outre, cela pourrait également permettre aux professionnels de santé de proposer un accompagnement particulier pour les personnes à faible niveau de LS afin d’améliorer leur état de santé et leur qualité de vie. / Health Literacy (HL) refers to the knowledge, motivation, and skills to access, understand, evaluate, and apply information in the health field. It is a major determinant of health that is frequently considered as a mechanism of the social inequities of health. The main objective of this thesis is to evaluate the association between HL, information inequities and the health status of people with cancer. However, given the lack of HL measuring instruments in France, we started with the psychometric validation of measurement tools.Our empirical work is based on analyzes of three surveys.These analyses allowed having valid French version of subjective scales measuring HL, numeracy and shared decision-making process. Our analyzes have shown that a limited level of HL is associated with less involvement in the shared decision process, more information seeking and impaired mental and physical health status. In addition, patients with limited level of HL consulted more often the general practitioner and the social worker. Considering the patients’ HL level during all the course of their care seems mandatory. This would allow information to be tailored to patients’ HL level, to reduce information inequities and increase patient participation in decision-making. In addition, this would also allow health professionals to propose special care for people with low levels of HL to improve their health and quality of life.

Hematopoiesis is a highly orchestrated process, in which a single hematopoietic stem cell (HSC) gives a rise to all blood cellular components. For myeloid and lymphoid development precise controlled expression of the PU.1 transcription factor is needed. Deletion of PU.1 gene in mouse is lethal and its dysregulation during hematopoietic differentiation is associated with blood malignancies including acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). MDS and AML are serious blood disorders characterized by expansion of immature blood cells and lack of differentiated functional cells. Not only genetic but also epigenetic aberrations represent a very important field for studying pathophysiology of leukemia genesis and dysregulation of the PU.1 gene represents intensively studied candidate mechanism. Modern therapy of selected MDS and subset of AML patients is based on treatment with DNA hypomethylating agent Azacytidine (AZA) interfering in PU.1 gene regulatory mechanism. However, poor response or resistance to this therapy often occurs. In this thesis we present data obtained from AZA-resistant clones of MDS/AML cell line OCI-M2. We analysed DNA methylation and DNA hydroxymethylation at the key regulatory element of the PU.1 gene (URE). We found that these epigenetic modifications at URE...

61 Summary Wilms' tumor gene 1 (WT1) is highly expressed in acute leukemia and other hematological malignancies. It has been therefore suggested as a potential universal marker of minimal residual disease (MRD), particularly in patients with acute myeloid leukemia (AML). Due to controversial results of some of the studies, the role of WT1 in MRD follow-up and WT1 prognostic significance remain unclear. WT1 protein is produced in more than 36 different isoforms. These variants have distinct, partially overlapping functions and their ratio is supposed to influence the final effect of WT1. However, despite the increasing number of studies, the clinical impact of WT1 and its isoforms in acute leukemia have not yet been elucidated. We established a unique qPCR method to assess the expression pattern of the main 4 WT1 isoforms. Using this method, we determined the ratio of WT1 variants in the samples of patients with AML, myelodysplastic syndrome (MDS) and healthy controls. Our data showed that this pattern can distinguish among particular hematological malignancies, but lacks a prognostic significance. Within our international study group we determined the prognostic significance of total WT1 expression in childhood AML. Based on our results of a large cohort of patients we can conclude that WT1 expression at...

Parkinson's is a chronic, progressive, neurodegenerative disease. The most common treatment is levodopa/carbidopa, which suppresses the symptoms of the disease. In this report, a cost-utility analysis of the MyFID levodopa/carbidopa micro tablet dispenser has been conducted. The method used was a continuous-time Markov chain with states based on the score in MDS-UPDRS II and MDS-UPDRS III. The model was simulated over a time horizon of five years and was started at different disease severity levels. The results obtained from the simulations were a dominant ICER for all model versions except when the simulation was started in the earliest stages of the disease, where it was moderate to high. The conclusion was that the treatment method with the micro / Parkinsons är en kronisk, progressiv, neurodegenerativ sjukdom. Den vanligaste behandlingen är levodopa/carbidopa, som undertrycker symptomen av sjukdomen. I denna rapport har en kostnadsnyttoanalys av MyFID levodopa/ carbidopa-mikrotablettdispensern genomförts. Metoden som användes var en kontinuerlig Markovkedja med tillstånd baserade på poängen i MDS-UPDRS II och MDS-UPDRS III. Modellen simulerades över en tidsperiod av fem år och startades vid olika svårighetsgrader av sjukdomen. Resultaten som erhölls från simuleringarna visade en dominerande ICER för alla modellversioner förutom när simuleringen startades i de tidigaste stadierna av sjukdomen, där den visade en måttligt till hög kostnad. Slutsatsen var att behandlingen med hjälp av mikrotablettdispensern var kostnadseffektiv i de måttliga till senare stadierna av sjukdomen.