Previous data have unveiled a novel autoregulatory feedback loop between iASPP and p63 in the stratified epithelia; this involves two microRNAs, miR-574-3p and miR-720, and is critical for epidermal homeostasis. The iASPP oncoprotein, an inhibitory member of the ASPP (apoptosis stimulating protein of p53) family, is a key inhibitor of p53 and NF-κB and is highly expressed in many cancers. Non-melanoma skin cancer, comprising of cutaneous squamous carcinoma (cSCC) and basal cell carcinoma, is currently the most common malignancy in the UK. In view of this newly-identified iASPP-p63 axis, I hypothesised a potential role for dysregulation of this feedback loop in the pathogenesis of cSCC and aimed to assess the role of iASPP in human cSCC. Protein and mRNA expression patterns were assessed in a panel of 10 cSCC cell lines generated by our group. In addition, immunostaining of iASPP and p63 was performed in 107 cSCC clinical samples of variable differentiation status. The data reveal an overall increase in expression of iASPP and ΔNp63 in cSCC but also suggest a significant alteration of the cellular localisation of iASPP dependent on the differentiation status of the tumour. To further assess the effects mediated by the iASPP/p63 axis, iASPP and p63 have been silenced by RNAi technology in a subset of cSCC cell lines. Whilst data shows the direct effects of iASPP and p63 upon each other's expression are maintained in cSCC, epigenetic dysregulation of the feedback loop at the microRNA level may be occurring via a novel p63 regulator, miR-211-5p. Functionality of iASPP in cSCC (proliferation, apoptosis, cell motility/migration and invasiveness) provides evidence for a role of iASPP in preventing epithelial-mesenchymal transition in cSCC via a p63/miR-205-5. These findings provide potential future directions for development of clinical biomarkers and novel therapeutic targets for cSCC and may ultimately provide the tools for tackling the increasing morbidity and mortality associated with this malignancy.

Camundongos AIRmax e AIRmin diferem na sensibilidade à carcinogênese, sendo os AIRmin mais sensíveis à carcinogênese de pele devido ao seu fundo genético e um polimorfismo no gene Ahr. Mais que isso, estas linhagens possuem um desequilíbrio de frequência dos alelos do gene Slc11a1. Para estudar a interação dos alelos de resistência (R) ou suscetibilidade (S) do gene Slc11a1 com os loci de resposta inflamatória aguda dos animais AIRmax e AIRmin, foram produzidas sublinhagens homozigotas para estes alelos:AIRmaxRR, AIRmaxSS, AIRminRR e AIRminSS. Nosso objetivo foi investigar a diferença de sensibilidade à carcinogênese de pele induzida por DMBA nestas sublinhagens. A incidência de câncer de pele foi de 7% nos animais AIRminRR e de 13% nos animais AIRminSS.Os animais AIRmaxSS não apresentaram câncer de pele, mas a incidência de câncer em órgãos internos foi 100% nesta sublinhagem.Esses dados mostraram que os camundongos AIRmaxSS tem maior suscetibilidade à carcinogênese, sugerindo que o alelo S, no fundo genético AIRmax, pode influenciar na suscetibilidade ao câncer. / Mice AIRmax and AIRmin differ on sensibility to carcinogenesis. AIRmin mice are significantly more sensitive to skin carcinogenesis than AIRmax mice due to the genetic background and the polymorphism of aryl hydrocarbon receptor (Ahr) gene. Furthermore,these mice have an imbalance of frequency of Slc11a1 gene alleles.To study the interaction of resistant (R) or susceptible (S) Slc11a1 alleles with acute inflammatory reaction loci found in AIRmax and AIRmin mice, homozygous sublines for these alleles were produced: AIRmaxRR, AIRmaxSS, AIRminRR and AIRminSS. The objective of this study was to investigate the difference in skin carcinogenesis sensibility induced by DMBA agent in these sublines.The incidence of skin cancer was 7% in AIRminRR mice and 13% in AIRminSS mice.AIRmaxRR and AIRmaxSS mice did not show skin cancer, but the incidence of internal organs cancer was 100% only in AIRmaxSS mice. These data showed that AIRmaxSS animals have higher susceptibility, suggesting that the S allele in the AIRmax background could influence susceptible to cancer.

Camundongos AIRmax e AIRmin diferem na sensibilidade à carcinogênese, sendo os AIRmin mais sensíveis à carcinogênese de pele devido ao seu fundo genético e um polimorfismo no gene Ahr. Mais que isso, estas linhagens possuem um desequilíbrio de frequência dos alelos do gene Slc11a1. Para estudar a interação dos alelos de resistência (R) ou suscetibilidade (S) do gene Slc11a1 com os loci de resposta inflamatória aguda dos animais AIRmax e AIRmin, foram produzidas sublinhagens homozigotas para estes alelos:AIRmaxRR, AIRmaxSS, AIRminRR e AIRminSS. Nosso objetivo foi investigar a diferença de sensibilidade à carcinogênese de pele induzida por DMBA nestas sublinhagens. A incidência de câncer de pele foi de 7% nos animais AIRminRR e de 13% nos animais AIRminSS.Os animais AIRmaxSS não apresentaram câncer de pele, mas a incidência de câncer em órgãos internos foi 100% nesta sublinhagem.Esses dados mostraram que os camundongos AIRmaxSS tem maior suscetibilidade à carcinogênese, sugerindo que o alelo S, no fundo genético AIRmax, pode influenciar na suscetibilidade ao câncer. / Mice AIRmax and AIRmin differ on sensibility to carcinogenesis. AIRmin mice are significantly more sensitive to skin carcinogenesis than AIRmax mice due to the genetic background and the polymorphism of aryl hydrocarbon receptor (Ahr) gene. Furthermore,these mice have an imbalance of frequency of Slc11a1 gene alleles.To study the interaction of resistant (R) or susceptible (S) Slc11a1 alleles with acute inflammatory reaction loci found in AIRmax and AIRmin mice, homozygous sublines for these alleles were produced: AIRmaxRR, AIRmaxSS, AIRminRR and AIRminSS. The objective of this study was to investigate the difference in skin carcinogenesis sensibility induced by DMBA agent in these sublines.The incidence of skin cancer was 7% in AIRminRR mice and 13% in AIRminSS mice.AIRmaxRR and AIRmaxSS mice did not show skin cancer, but the incidence of internal organs cancer was 100% only in AIRmaxSS mice. These data showed that AIRmaxSS animals have higher susceptibility, suggesting that the S allele in the AIRmax background could influence susceptible to cancer.

No description available.

La spectroscopie vibrationnelle est une technologie permettant de générer une grande quantité de données très informatives quant à la composition moléculaire des échantillons analysés. Lorsqu'elle est couplée à des méthodes chimiométriques de traitement et de classification de données, elle devient un outil très performant pour l'identification de structures et sous-structures des échantillons. Appliqué dans le domaine du biomédical, cet outil présente alors un fort potentiel pour le diagnostic de maladie. C'est dans ce cadre qu'ont été réalisés les travaux de ce manuscrit. Dans une première étude relevant du développement algorithmique, un algorithme automatique de classification non supervisée (basé sur les Fuzzy C-Means) et récemment implémenté au sein du laboratoire pour apporter une aide au diagnostic de cancers cutanés par imagerie infrarouge, a été amélioré afin de i) considérablement réduire le temps nécessaire à son exécution ii) augmenter la qualité des résultats obtenus sur les données infrarouge et iii) étendre son champs d'application à des données réelles et simulées, habituellement employées dans la littérature. Cet outil a été testé sur des données infrarouge acquises sur 16 échantillons de cancers cutanés (BCC, SCC, maladie de Bowen et mélanomes), et sur 49 jeux de données réels et simulés. Les résultats obtenus ont montré la capacité de ce nouvel algorithme à estimer des partitions proches de la réalité quelque soit le type de données étudié. La seconde étude de ce manuscrit avait pour but de mettre au point un outil chimiométrique autonome d'aide au diagnostic de la leucémie lymphoïde chronique par spectroscopie Raman. Dans ce travail, des traitements numériques et l'algorithme de classification supervisée Support Vector Machines, ont été appliqués à des données acquises sur des cellules sanguine de 27 témoins et 49 patients présentant une leucémie lymphoïde chronique. Les résultats de classification obtenus ont montré une sensibilité de 80% et une spécificité de 100% dans la détection de la maladie. / Vibrational spectroscopy is a technology able to record a large amount of molecular information from studied samples. Coupled with chemometrics and classification methods, vibrational spectroscopy is an efficient tool to identify sample structures and substructures. When applied to the biomedical field, this tool shows a high potential for disease diagnosis. It is in this context that the works presented in this thesis have been realized. In a first study, dealing with algorithmic development, an automatic and unsupervised classification algorithm (based on the Fuzzy C-Means) and developed by our laboratory in order to help for skin cancer diagnosis using IR spectroscopy, was improved in order to i) reduce the computational time needed to realize clustering, ii) increase results quality obtained on infrared data, iii) and extend its application fields to simulated and real datasets, commonly used in the literature. This tool has been tested on 16 infrared spectral images of skin cancers (BCC, SCC, Bowen's disease and melanoma), and 49 real and simulated datasets. The obtained results showed the ability of this new algorithm to estimate realistic data partitions regardless the considered dataset. The second study of this work aimed at developing an independent chemometric tool to assist for chronic lymphocytic leukemia diagnosis by Raman spectroscopy. In this second work, different numerical preprocessing steps and a supervised classification algorithm, Support Vector Machines, have been applied on data recorded on blood cells coming from 27 healthy persons and 49 patients with chronic lymphocytic leukemia. The classification results showed a sensitivity of 80% and a specificity of 100% in the disease diagnosis.

A previous population-based study of survival in Chronic Lymphocytic Leukemia (CLL) patients in the province of Manitoba demonstrated a lower five-year relative survival among CLL patients compared with the age- and gender-adjusted general population. This decreased relative survival was most pronounced among elderly male CLL patients. In this study, we have demonstrated that the reduced five-year relative survival observed in CLL patients compared to the general population of Manitoba may partially be attributed to increased risk of second cancers and non-referral to specialized CLL clinics. The increased risk of second cancers in CLL patients compared to Follicular Lymphoma (FL), a similar indolent B cell malignancy, was only observed after CLL diagnosis indicating that a CLL-specific factor may be responsible for the increased risk of second cancers in these patients. The risk of second cancers is independent of treatment and surveillance bias but is further increased with chemotherapy. A superior outcome in CLL patients who have been referred to the CancerCare Manitoba (CCMB) specialized CLL clinic was observed that was independent of age, gender, treatment and history of previous cancers. This superior outcome was most pronounced in the elderly CLL patients. We propose that CLL patients should be referred to CLL-specific hematologists and, where not possible, that guidelines created by such experts be followed. Appropriate screening for second cancers should be performed during routine follow up of CLL patients.

In this thesis I explore sunscreen use-practices, imaginaries, and material flows. I aim to understand how young people in the globally-immersed UK use sunscreens and how they makesense of them. Specifically, I follow Donna Haraway’s practice of implosion, employing theconcepts of care and toxicity to explore how sunscreens are employed to protect particularbodily ideals, aspects of embodied subjectivities and material-discursive boundaries. In following these various forms of protection, I ask what normative discourses, ecologies andbodies are, in turn, made vulnerable. The main corpus of my study comes from interviewconversations with eight people. Their stories highlight how sunscreens mediate understandings of skin, places, bodies, and social relations. I analyse sunscreen advertising from 1979to 2019 to investigate harmonies and conflicts between the cultural imaginaries curated bysunscreen companies and the stories which emerged from these interview conversations. Ialso put these materials into conversation with sunscreen discourses from the biological sciences, asking how these cultural works infuse sunscreen practices and material-semiotics.This thesis is an exploratory journey which encounters tanning, ageing, beauty, ‘race’,smells, places, intimacies, sun-burns, skin cancers, bodily boundaries, ‘Endocrine Disruptors’, toxic ecologies, and emplaced knowledges. It traverses disciplinary boundaries, following attitudes from the feminist and environmental post-humanities in bringing togetherapproaches, methods and theorising from many varied fields of scholarship usually locatedin the humanities, social sciences, and ‘natural’ sciences. As such, this thesis is a wide-ranging, thick description of how sunscreens are used in desires for protection and what is contingently and consequently made vulnerable.

Contexte : Les cancers cutanés sont les cancers les plus fréquents dans les populations de peau blanche. Si l’exposition aux rayonnements ultraviolets est le facteur de risque le plus connu, peu d’études ont permis une comparaison directe des profils d’exposition solaire associés à ces tumeurs dans une même population, et les déterminants des comportements d’exposition solaire restent peu connus à ce jour. Par ailleurs, bien que les antioxydants, ayant la capacité de neutraliser les radicaux libres, représentent des candidats potentiels pour la chimioprévention des cancers cutanés, l’état actuel des connaissances ne permet pas d’émettre de conclusion claire en ce qui concerne leur rôle vis-à-vis du risque de cancers cutanés.Objectif : L’objectif de cette thèse est de préciser le lien existant entre l’exposition solaire et le risque de cancers cutanés, d’explorer les profils associés à certains comportements d’exposition solaire et d’étudier les associations potentielles entre compléments alimentaires en antioxydants et risque de cancers cutanés dans l’étude française E3N (Étude Épidémiologique auprès de femmes de l’Éducation Nationale).Résultats : Nos résultats suggèrent que les trois types de cancers cutanés sont associés à différents profils d'exposition solaire et que l’utilisation de crème solaire, de lampes UV et de compléments solaires sont associés à plusieurs habitudes favorables et défavorables pour la santé. De plus, nos résultats suggèrent que les consommations de compléments solaires et de compléments en vitamine E sont associées à un risque accru de carcinomes cutanés.Conclusion : Ce travail souligne l’importance de la prévention pour réduire la prévalence des cancers cutanés ainsi que la nécessité de mieux comprendre les profils associés à différents comportements d’exposition solaire et leur impact potentiel sur les associations avec le risque de cancers cutanés. Par ailleurs, nos résultats ne soutiennent pas l’hypothèse d’un effet protecteur de la consommation de compléments alimentaires en antioxydants vis-à-vis du risque de cancers cutanés et appellent à davantage de recherches afin de mieux comprendre leurs effets à long terme sur la santé. / Background: Skin cancers are the most common cancers in white-skinned populations. While exposure to solar radiation is the best known risk factor, few studies have allowed a direct comparison of exposure profiles associated with these tumours within a single population, and little is known about the determinants of sun exposure behaviors. Moreover, although antioxidants, which have the ability of scavenging free radicals, are potential candidates for the chemoprevention of skin cancers, the current state of the literature does not allow to make clear conclusions with regards to their role on skin cancer risk.Objectives: The objective of this thesis is to examine the associations between UV exposures and skin cancer risk, to describe the profiles associated with several sun exposure behaviors, and to explore the potential associations between antioxidant dietary supplements and the risk of skin cancer in the French E3N (Étude Épidémiologique auprès de femmes de l’Éducation Nationale) study.Results: Our results suggest that the three types of skin cancers are associated with different sun exposure profiles and that sunscreen use, sunbed use, and solar supplement use are associated with both healthy and risky behaviors. In addition, our findings suggest that the use of solar supplements and vitamin E supplements is associated with an increased risk of non-melanoma skin cancers.Conclusions: This work emphasizes the importance of prevention to reduce the prevalence of skin cancers as well as the need to better understand the profiles associated with sun exposure behaviors and their potential impact on the associations with the risk of skin cancer. Furthermore, our results do not support the hypothesis of a protective effect of the consumption of antioxidant dietary supplements on the risk of skin cancer and call for more research in order to better understand their long-term effects on health.