A terapia fotodinâmica (TFD) é uma modalidade clínica para tratar uma variedade de neoplasias, doenças de pele e representa um promissor tratamento estético. O presente trabalho avaliou os aspectos histopatológicos e moleculares do tratamento pela TFD mediada por azul de metileno (TFD-AM) no modelo experimental in vivo do Carcinoma Espinocelular Cutâneo (CEC) e na pele sadia de camundongos Swiss. O protocolo da TFD foi de uma única sessão, com aplicação da solução de AM a 1% seguido por irradiação com laser diodo na dose total de 24 J/cm2 nos tecidos tumorais e sadios. Os animais foram sacrificados em dois períodos, 24 horas e 15 dias após TFD. Alterações morfológicas foram pouco marcantes nos tecidos tumorais tratados, entretanto, foram mais pronunciadas nos tecidos sadios. Podemos concluir que os efeitos de uma única sessão da TFD mediada pelo AM na dose aplicada não conferiu melhora no tratamento do CEC. Estes resultados motivam novos estudos com ajustes no protocolo para melhorar a eficácia desta terapia. / Photodynamic therapy (PDT) is a clinical method for treating a variety of tumors, skin disorders and represents a promising cosmetic treatment. This study evaluated the histopathological and molecular aspects of the treatment by PDT mediated by methylene blue (PDT-MB) in vivo experimental model of cutaneous squamous cell carcinoma (SCC) and in healthy skin of swiss mice. The PDT protocol was a single session with the application of MB 1% solution followed by irradiation with diode laser at a total dose of 24 J/cm2 in tumor and healthy tissue. The animals were sacrificed at two periods, 24 hours and 15 days after PDT. Morphological changes were less marked in the tumor tissues treated, however, were more pronounced in healthy tissues treated. We can conclude that the effects of a single session of PDT mediated by MB in applied dose conferred no improvement in the treatment of SCC. These results motivate further studies with adjustments in the protocol to improve the effectiveness of this therapy.

Doenças crônicas sistêmicas, em especial o diabetes mellitus, favorecem o aparecimento e a continuidade de lesões dermo-epidérmicas, sendo o impacto econômico e social significativo. No âmbito da medicina regenerativa para o tratamento de lesões cutâneas crônicas, o emprego clínico da bioengenharia de tecidos associada à terapia celular tem sido considerado uma promissora alternativa terapêutica. Neste contexto, o estudo tem como objetivo avaliar a eficácia terapêutica no tratamento de úlceras cutâneas de pacientes diabéticos, empregando células-tronco mesenquimais do tecido adiposo (CT-TA) associadas a plasma rico em plaquetas (PRP) obtido de sangue autólogo. A pesquisa aplicada foi composta por seis pacientes diabéticos e portadores de úlceras cutâneas crônicas. A reepitelização total ocorreu em 5 das 9 lesões tratadas, sendo o índice de cicatrização médio superior a 70% após 3 meses da aplicação. Desta forma, é possível concluir que a terapia com CT-TA associadas a PRP proporciona uma redução na área ulcerosa de lesões cutâneas crônicas em pacientes diabéticos. / Systemic chronic diseases, especially diabetes mellitus, favor the emergency and continuity of dermal-epidermal lesions, being significant the economic and social impact. Within the regenerative medicine field for treatment of cutaneous chronic wounds, the clinical use of tissue bioengineering and cell therapy has been considered as a promising therapeutic alternative. In this context, the present study aims to evaluate the therapeutic efficiency, using adipose-derived mesenchymal stem cells (ADSC) associated with platelet-rich plasma (PRP) obtained from autologous blood, for the treatment of cutaneous ulcers from diabetic patients. The applied research was composed of six diabetic patients with chronic skin ulcers. The total re-epithelialization occurred in 5 of the 9 lesions treated, and the average wound healing index greater than 70% after 3 months of application. In this way, it can be concluded that ADSC therapy associated with PRP provides a reduction in ulcer area of chronic skin lesions in diabetic patients.

Made available in DSpace on 2016-01-26T18:55:39Z (GMT). No. of bitstreams: 1 Karina.pdf: 2597948 bytes, checksum: d65c6af5a956ec0d8f0afae614fe6d8a (MD5) Previous issue date: 2014-03-17 / The platelet rich plasma is a source of several growth factors and appears as a new biotechnology in tissue repair, with great therapeutic power. Patients with general health problems and the lack of volume of blood required for autologous production of concentrate, may be restricted to receive this innovative treatment. To overcome the limitation, this study evaluated the effects of heterologous platelet-rich plasma gel obtained from a healthy dog, in the healing of dermal wounds in rabbits by standard morphological, morphometric and histological analyzes. Two surgical incisions were made on the back of six rabbits using a punch of 8 mm diameter. Randomly one side was denominated as a Control (A), leaving the contralateral Treaty as (B). 0.9% saline solution and heterologous platelet-rich plasma gel were applied topically to the lesions (A) and (B) respectively, on days 0, 3, 7, 10 and 14 after surgery. Macroscopic observations recorded on the days mentioned above, including the 17th, which is also a biopsy for histological analysis was performed, demonstrated similarity between the lesions in relation to the study variables, pain sensitivity, color of wound edema, hyperemia, exudate, crust and granulation tissue. The process of contraction of the lesion area (A) and (B) similarly developed linearly, so that histologically complete reepithelialization was achieved in 90% of lesions (A) and 100% of the lesions (B), no differences statistically significant. Such differences were also not found between wounds in relation to other histological parameters analyzed: presence of crust, neovascularization, collagen, fibroblasts and macrophages, cell type and intensity of the inflammatory process. The results of this study suggest that the heterologous platelet-rich plasma gel was able to promote the healing of dermal wounds in rabbits, no harmful effects. / O plasma rico em plaquetas é fonte de diversos fatores de crescimento e surge como uma nova biotecnologia na reparação tecidual, com grande potencial terapêutico. Pacientes com problemas de saúde geral e ausência de volume de sangue necessário para produção autóloga deste concentrado, podem ficar limitados para receber este tratamento inovador. Para ultrapassar a limitação, o presente estudo avaliou os efeitos do gel de plasma rico em plaquetas obtido a partir de um cão saudável, na cicatrização de feridas dérmicas padronizadas em coelhos mediante análises morfológicas, morfométricas e histológicas. Foram produzidas duas incisões no dorso de seis coelhos utilizando punch de 8 mm de diâmetro. Aleatoriamente, um dos lados foi denominado Controle (A), permanecendo o contralateral Tratado (B). Solução fisiológica a 0.9% e gel de plasma rico em plaquetas heterólogo foram aplicados topicamente nas lesões (A) e (B) respectivamente, nos dias 0, 3, 7, 10 e 14 de pós-operatório. Observações macroscópicas registradas nos dias mencionados acima, incluindo o 17o, no qual também foi realizada uma biópsia para análise histológica, demonstraram semelhança entre as lesões em relação às variáveis estudadas, sensibilidade dolorosa, cor da ferida, edema, hiperemia, exsudato, crosta e tecido de granulação. O processo de contração da área das lesões (A) e (B) evoluiu similarmente de forma linear, de modo que, histologicamente, reepitelização total foi alcançada em 90% das lesões (A) e 100% das lesões (B), sem diferenças estatisticamente significantes. Tais diferenças também não foram constatadas entre as feridas em relação aos demais parâmetros histológicos analisados: presença de crosta, neovascularização, colagenização, quantidade de fibroblastos e macrófagos, tipo celular e intensidade do processo inflamatório. Os resultados desta pesquisa sugerem que o gel de plasma rico em plaquetas heterólogo foi capaz de promover a cicatrização de feridas dérmicas em coelhos, sem efeitos prejudiciais.

Made available in DSpace on 2016-07-18T17:53:12Z (GMT). No. of bitstreams: 1 Karina.pdf: 2597948 bytes, checksum: d65c6af5a956ec0d8f0afae614fe6d8a (MD5) Previous issue date: 2014-03-17 / The platelet rich plasma is a source of several growth factors and appears as a new biotechnology in tissue repair, with great therapeutic power. Patients with general health problems and the lack of volume of blood required for autologous production of concentrate, may be restricted to receive this innovative treatment. To overcome the limitation, this study evaluated the effects of heterologous platelet-rich plasma gel obtained from a healthy dog, in the healing of dermal wounds in rabbits by standard morphological, morphometric and histological analyzes. Two surgical incisions were made on the back of six rabbits using a punch of 8 mm diameter. Randomly one side was denominated as a Control (A), leaving the contralateral Treaty as (B). 0.9% saline solution and heterologous platelet-rich plasma gel were applied topically to the lesions (A) and (B) respectively, on days 0, 3, 7, 10 and 14 after surgery. Macroscopic observations recorded on the days mentioned above, including the 17th, which is also a biopsy for histological analysis was performed, demonstrated similarity between the lesions in relation to the study variables, pain sensitivity, color of wound edema, hyperemia, exudate, crust and granulation tissue. The process of contraction of the lesion area (A) and (B) similarly developed linearly, so that histologically complete reepithelialization was achieved in 90% of lesions (A) and 100% of the lesions (B), no differences statistically significant. Such differences were also not found between wounds in relation to other histological parameters analyzed: presence of crust, neovascularization, collagen, fibroblasts and macrophages, cell type and intensity of the inflammatory process. The results of this study suggest that the heterologous platelet-rich plasma gel was able to promote the healing of dermal wounds in rabbits, no harmful effects. / O plasma rico em plaquetas é fonte de diversos fatores de crescimento e surge como uma nova biotecnologia na reparação tecidual, com grande potencial terapêutico. Pacientes com problemas de saúde geral e ausência de volume de sangue necessário para produção autóloga deste concentrado, podem ficar limitados para receber este tratamento inovador. Para ultrapassar a limitação, o presente estudo avaliou os efeitos do gel de plasma rico em plaquetas obtido a partir de um cão saudável, na cicatrização de feridas dérmicas padronizadas em coelhos mediante análises morfológicas, morfométricas e histológicas. Foram produzidas duas incisões no dorso de seis coelhos utilizando punch de 8 mm de diâmetro. Aleatoriamente, um dos lados foi denominado Controle (A), permanecendo o contralateral Tratado (B). Solução fisiológica a 0.9% e gel de plasma rico em plaquetas heterólogo foram aplicados topicamente nas lesões (A) e (B) respectivamente, nos dias 0, 3, 7, 10 e 14 de pós-operatório. Observações macroscópicas registradas nos dias mencionados acima, incluindo o 17o, no qual também foi realizada uma biópsia para análise histológica, demonstraram semelhança entre as lesões em relação às variáveis estudadas, sensibilidade dolorosa, cor da ferida, edema, hiperemia, exsudato, crosta e tecido de granulação. O processo de contração da área das lesões (A) e (B) evoluiu similarmente de forma linear, de modo que, histologicamente, reepitelização total foi alcançada em 90% das lesões (A) e 100% das lesões (B), sem diferenças estatisticamente significantes. Tais diferenças também não foram constatadas entre as feridas em relação aos demais parâmetros histológicos analisados: presença de crosta, neovascularização, colagenização, quantidade de fibroblastos e macrófagos, tipo celular e intensidade do processo inflamatório. Os resultados desta pesquisa sugerem que o gel de plasma rico em plaquetas heterólogo foi capaz de promover a cicatrização de feridas dérmicas em coelhos, sem efeitos prejudiciais.

No description available.

Oncogenic microRNAs (miRNAs) are small RNA molecules that inhibit post-translational regulatory mechanisms at the epigenetic level. miRNAs are often deregulated in malignancies and due to their stability are detectable in non-cellular fractions of peripheral blood. In our laboratory, we have performed several studies that have investigated and utilized miRNAs as biomarkers for various hematological tumors (e.g., chronic lymphocytic leukemia, Hodgkin`s lymphoma) and solid tumors (e.g., breast cancer). The aim of these studies was to find the association of miRNAs with pathophysiological and clinical aspects of each disease. Here, we confirmed the importance of particular miRNA or its complex during disease monitoring. Combining clinical, molecular biological and statistical analyses, we were able to find miRNA sets that fulfilled not only a diagnostic role but also a prognostic role beyond expectations. The main focus of this thesis is on the investigation of microRNAs in the diagnosis of a hematological malignancy - primary cutaneous T-cell lymphoma (CTCL). Tumor specificity of some miRNAs has been demonstrated. Their aberrant expression in tissue samples of CTCL patients obtained from skin biopsies, correctly distinguished malignant disease from control samples of benign skin lesions. Here, we...

Antecedentes: La leishmaniasis es considerada una enfermedad endémica en nuestro país; sin embargo, su estudio en nuestro medio aún es incipiente. Objetivos: Determinar los diferentes factores asociados a la falla del tratamiento con estibogluconato de sodio en pacientes diagnosticados de leishmaniasis cutánea que fueron tratados en el Hospital Nacional “Arzobispo Loayza” (HNAL) en Lima, Perú, durante los años 2006-2018. Materiales y métodos: Se realizó un estudio retrospectivo de casos y control anidado a una cohorte de 100 pacientes con diagnóstico de leishmaniasis cutánea que tuvieron tratamiento con estibogluconato de sodio en el HNAL. Los 28 casos fueron los pacientes que fallaron al tratamiento y los 72 controles fueron los pacientes que tuvieron una buena respuesta clínica. Se comparó ambos grupos y se empleó la regresión logística para obtener los Odds ratio e intervalos de confianza al 95%. Resultados: La proporción de falla al tratamiento en el HNAL entre los años 2006 y 2018 fue de 28%. Los pacientes que fallaron al tratamiento tuvieron mayor probabilidad de proceder de la costa en comparación con los pacientes que no fallaron al tratamiento (OR 6,8 IC 95% 1,75 - 26,3 p<0,05). Asimismo, los pacientes que fallaron al tratamiento tuvieron mayor probabilidad de haber presentado una lesión única en comparación de los pacientes que no fallaron al tratamiento (OR 4,0 IC 95% 1,11 - 15,0 p= 0,03). Conclusión: Este estudio encontró que la proporción de fracaso del tratamiento fue ligeramente superior a estudios previos. Asimismo, los pacientes que fallaron al tratamiento tuvieron mayor probabilidad de proceder de la costa y haber presentado una lesión única. Se recomienda realizar estudios multicéntricos donde se pueda evaluar esta asociación. / Background: Leishmaniasis is considered an endemic disease in our country; however, its study in our environment is still incipient. Objectives: To determine the different factors associated with the failure of sodium stibogluconate treatment in patients diagnosed with cutaneous leishmaniasis who were treated at the “Arzobispo Loayza” National Hospital (HNAL) in Lima, Peru, during the years 2006-2018. Materials and methods: A nested retrospective case-control study was conducted in a cohort of 100 patients diagnosed with cutaneous leishmaniasis who underwent sodium stibogluconate treatment at the HNAL. The 28 cases were the patients who failed the treatment, and the 72 controls were the patients who had a good clinical response. Both groups were compared, and logistic regression was used to obtain the Odds ratio and 95% confidence intervals. Results: The proportion of treatment failure in the HNAL between 2006 and 2018 was 28%. Patients who failed treatment had more probability to proceed to coast compared with patients who didn't fail treatment (OR 6,8 IC 95% 1,7 - 26,3 p<0,05). Likewise, the patients who failed treatment had more probability to had got only one injury compared with patients who didn't fail treatment. (OR 4,0 IC 95% 1,1 - 15,0 p= 0,03), Conclusion: This study found that the rate of treatment failure was slightly higher than previous studies. Likewise, the patients who failed treatment had more probability to proceed from coast and had got only one injury. It is recommended to carry out multicenter studies where this association can be evaluated. / Tesis

Crèmes, shampooings, savons, gels douche, ces produits cosmétiques quotidiennement utilisés, ont en commun la présence d'une matière première essentielle à leur formulation, à savoir le tensioactif ou émulsionnant. Ces molécules sont donc fréquemment en contact avec la peau. En effet, de par sa structure amphiphile particulière, le tensioactif aide à la stabilisation des émulsions, permet la formation de mousse et apporte les propriétés détergentes des produits cosmétiques nettoyants, en solubilisant les corps gras présents en surface. Ces molécules peuvent également interagir avec les composants de la peau. Une des premières preuves évidentes de l'interaction des tensioactifs avec la peau est l'observation des signes cliniques suite à l'exposition prolongée ou chronique à des formules riches en tensioactifs. Ces molécules sont maintenant connues pour engendrer des dermatites de contact d'irritation et font l'objet d'un véritable problème de santé publique concernant les maladies professionnelles aux détergents. Cependant, devant la multitude de tensioactifs présents sur le marché, les mécanismes d'action des tensioactifs sur la peau sont encore mal connus, surtout pour les tensioactifs non ioniques, très utilisés dans les produits de soin et souvent considérés comme non toxiques. Le sodium lauryl sulfate, tensioactif anionique reste à ce jour, la molécule modèle couramment étudiée. La toxicité cutanée est le plus souvent reliée à l'interaction du tensioactif avec les protéines, molécules chargées. De ce fait, les tensioactifs ioniques sont considérés comme étant les plus toxiques pour la peau. De plus, la forme monomérique du tensioactif est décrite comme l'entité responsable de la toxicité cutanée, s'insérant plus facilement dans la bicouche lipidique et pouvant ainsi pénétrer plus facilement dans la peau que sous la forme de micelles. La toxicité du tensioactif est donc également reliée à sa concentration micellaire critique. L'objectif de ce projet de recherche était d'approfondir les connaissances sur différentes propriétés physicochimiques de nombreuses classes de tensioactifs, afin de mieux comprendre leurs interactions ainsi que leurs effets sur la peau. Plusieurs niveaux d'études ont été développés. Après une analyse physicochimique des tensioactifs détaillée, des mesures in vitro ont permis d'évaluer l'effet du tensioactif sur la toxicité cutanée. L'étude portant sur la fonction barrière de la peau (propriétés de surface/détergence, organisation de la matrice lipidique et évaluation de l'extraction lipidique) a été menée via des expérimentations ex vivo. Nos études ont montré une toxicité notable de certains tensioactifs non ioniques et a contrario certains tensioactifs ioniques se sont révélés parfaitement bien tolérés. Les paramètres soulignés dans la littérature tels que la CMC et la charge des tensioactifs ont été remis en question. Plusieurs explications ont été mises en avant considérant l'organisation du tensioactif dans l'eau et son comportement vis-a-vis de la fonction barrière cutanée apportant ainsi de nouvelles pistes pour une meilleure compréhension de l'effet du tensioactif sur la peau. De plus La toxicité des tensioactifs a pu être reliée à un des trois niveaux de perturbation de la barrière cutanée: la désorganisation de la matrice lipidique / Creams, shampoos, soaps, shower gels, these cosmetics daily used, have in common the presence of a raw material essential to their formulation, namely the surfactant or emulsifier. These molecules are therefore frequently in contact with the skin. Indeed, because of its particular amphiphilic structure, the surfactant helps the stabilization of emulsions, allows the formation of foam and provides the detergent properties of cleansing cosmetic products, by solubilizing the fatty substances present on the surface. These molecules can also interact with the components of the skin. One of the first obvious evidence of the interaction of surfactants with the skin is the observation of clinical signs following prolonged or chronic exposure to surfactant-rich formulas. These molecules are now known to cause irritant contact dermatitis and are the subject of a real public health problem regarding professional detergent diseases. However, considering the multitude of surfactants on the market, the mechanisms of action of surfactants on the skin are still poorly known, especially for nonionic surfactants, widely used in skincare products and often considered non-toxic. Sodium lauryl sulfate, anionic surfactant remains to this day, the model molecule currently studied. The cutaneous toxicity is most often related to the interaction of the surfactant with the proteins, charged molecules. As a result, ionic surfactants are considered to be the most toxic to the skin. In addition, the monomeric form of the surfactant is described as the entity responsible for cutaneous toxicity, fitting more easily into the lipid bilayer and thus able to penetrate the skin more easily than in the form of micelles. The toxicity of the surfactant is therefore also related to its critical micelle concentration. . The objective of this research project was to expand knowledge on different physicochemical properties of many classes of surfactants, to better understand their interactions and their effects on the skin. Several levels of studies have been developed. After detailed physicochemical analysis of the surfactants, in vitro measurements were used to evaluate the effect of the surfactant on skin toxicity. The study on the skin barrier function (surface properties / detergency, lipid matrix organization and evaluation of lipid extraction) was conducted via ex vivo experiments. Our studies have shown significant toxicity of some nonionic surfactants and conversely some ionic surfactants have been found to be perfectly well tolerated. Parameters highlighted in the literature such as CMC and surfactant charges have been questioned. Several explanations were put forward considering the organization of the surfactant in the water and its behavior on the skin barrier function thus bringing new tracks for a better understanding of the effect of the surfactant on the skin. In addition, the toxicity of the surfactants could be related to one of the three levels of disruption of the cutaneous barrier: the disorganization of the lipid matrix

De nombreux systèmes nanoparticulaires ont été développés pour modifier la délivrance de molécules par la voie cutanée. Dans ce travail de thèse, nous nous sommes intéressés aux nanoparticules lipidiques type Janus (JNP), une forme galénique innovante caractérisée par la combinaison de deux compartiments, de polarité chimique opposée, un compartiment aqueux accolé à un compartiment lipidique. L’objectif principal a été la caractérisation des JNP. La spectroscopie ATR-FTIR a permis de mettre au point un descripteur IR permettant de suivre la stabilité physique des JNP à l’air libre et en fonction du temps. Le même descripteur a permis de suivre leur devenir à la surface de la peau, et de constater une pénétration significative à partir de 3 heures d’application. Nous avons prouvé que l’AFM-IR est une technique prometteuse pour étudier la nanostructure de la peau. De plus, elle a permis de montrer qu’après 24 heures d’application, les JNP se sont accumulées dans les premières couches du SC avec un gradient dans les couches plus profondes du SC. En revanche, il n’a pas été possible de déterminer si elles ont pénétré à l’état intact ou dégradé. Les JNP semblent avoir une influence sur la pénétration cutanée de l’acide hyaluronique, elles ont permis une augmentation significative de son flux de pénétration. La caractérisation de la phase lipophile des JNP par différentes techniques (LC-MS, DLS, Cryo-TEM, diffraction des rayons X…) a permis de mieux comprendre leur instabilité aux températures élevées (32°C - 43°C). / Many nanocarriers have been developed to improve the delivery of molecules into the skin. In this PhD thesis, we are interested in lipid-based Janus nanoparticles (JNP), an innovative galenic form characterized by the combination of two compartments of opposite chemical polarity, an aqueous compartment associated to a lipid compartment. The main aim was the characterization of JNP. ATR-FTIR spectroscopy allowed to identify an infrared descriptor to follow the physical stability of JNP in open air and over time. The same descriptor allowed to follow their behavior on the surface of the skin, and to note a significant penetration from 3 hours of application. AFM-IR has been shown to be a promising technique for studying the nanostructure of the human skin. In addition, it has shown that after 24 hours of application, JNP were accumulated in the first layers of the SC with a gradient in the deeper layers of the SC. However, it was not possible to conclude if they have penetrated in the intact or degraded form. JNP seem to have an influence on the cutaneous penetration of the hyaluronic acid, they allowed a significant increase of its penetration flux. The characterization of the lipophilic phase of JNP by different techniques (LC-MS, DLS, Cryo-TEM, X-ray diffraction...) allowed to better understand their instability at high temperatures (32°C - 43°C).

Tesis por compendio / [ES] El melanoma es el tipo de cáncer de piel más mortífero y peligroso, ya que tumores de pequeño tamaño pueden generar metástasis. Hasta la fecha, se ha tratado de clasificar desde el punto de vista clínico, epidemiológico y molecular, empleándose actualmente el nivel de exposición solar y la localización del tumor como criterios principales para dividir en distintos grupos a los pacientes de melanoma. En 1998, David Whiteman y colaboradores propusieron un "modelo de vías divergentes" para el desarrollo del melanoma. Este presentaba dos vías: una vinculada a la proliferación melanocítica (nevogénica) y otra relacionada con la exposición solar crónica (CSD). Corroborado desde el punto de vista clínico y epidemiológico, todavía no se ha aportado una caracterización molecular en profundidad. A nivel general se habían identificado genes cuyas mutaciones eran relevantes para el desarrollo del melanoma, como por ejemplo KIT. Sin embargo, todavía se había de estudiar con más detalle la distribución de estas mutaciones entre los distintos subgrupos de melanoma, así como su posible valor pronóstico. En esta tesis se han empleado técnicas de secuenciación - masiva y tradicional - para caracterizar los perfiles mutacionales de las poblaciones del modelo de vías divergentes. Encontramos diferencias tanto en el número de mutaciones como en los genes afectados. También hemos visto cómo los melanomas con mutaciones en KIT parecen desarrollarse por una vía independiente de la etiopatogenia conocida, careciendo el estatus mutacional de este gen de valor pronóstico para la supervivencia de los pacientes. / [CA] El melanoma és el tipus de càncer de pell més mortífer i perillós, ja que fins els tumors de menor mida poden acabar generant metàstasi. Al llarg dels anys, s'ha tractat de classificar des del punt de vista clínic, epidemiològic i molecular. Les classificacions actuals utilitzen el nivell d'exposició solar i la localització tumoral per dividir en diferents grups als pacients de melanoma. Al 1998, David Whiteman i col·laboradors proposaren un model de desenvolupament del melanoma que anomenaren "model de vies divergents". Aquest presentava dos vies per la melanomagènesi: una vinculada a la proliferació melanocítica (nevogènica) i l'altra relacionada amb l'exposició solar crònica (CSD). Malgrat aquest model fou corroborat des del punt de vista clínic i epidemiològic, encara no s'ha aportat una caracterització molecular en profunditat. A nivell general s'havien identificat gens les mutacions dels quals eren rellevants per al desenvolupament del melanoma, com el gen KIT. Però, encara s'havia d'estudiar amb més cura la distribució d'estes mutacions entre els distints subgrups de melanoma, així com el seu possible valor pronòstic. En aquesta tesi s'han emprat tècniques de seqüenciació -massiva i tradicional- per caracteritzar els perfils mutacionals de les dues poblacions proposades pel model de vies divergents, trobant diferències tant al nombre de mutacions com als gens afectats. També hem vist com els melanomes mutats en KIT semblen desenvolupar-se per una via independent de l'etiopatogènia coneguda, mancant l'estatus mutacional d'aquest gen de valor pronòstic per la supervivència dels pacients. / [EN] Melanoma is the deadliest and most dangerous type of skin cancer, given that a small tumor can spread and result in metastasis. Over the years, classifications have been made either from a clinical, epidemiological or molecular point of view. Current classifications use the degree of solar exposure and tumoral location to divide into different melanoma groups. In 1998, David Whiteman and collaborators proposed the divergent pathway model for melanoma development. This presented two pathways to melanomagenesis: one related to melanocytic proliferation (nevogenic) and the other related to chronic sun exposure (CSD). Despite corroborations of this model from the clinic and epidemiology, it is yet to be molecularly characterized in depth. At a general level, different genes had been identified with relevant mutations for the development of melanoma, as is the gene KIT. However, there was a lack of knowledge on how these mutations were distributed among different melanoma subgroups, as well as the potential prognostic value. In this thesis we have implemented sequencing techniques - both massive and traditional - to characterize the mutational profile of the two populations proposed by the divergent pathways model. We found differences both in the number of mutations and in the genes carrying the mutations. We have also seen how melanomas harboring KIT mutations seem to develop in a way which is independent from the known etiology, and how the mutational status of this gene lacks prognostic value on the outcome of the patients. / Millán Esteban, D. (2022). Next-Generation Sequencing in the Identification of Biomarkers in Cutaneous Melanoma According to the Etiopathogenic Development Pathway and their Potential Clinical Relevance [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/182977 / TESIS / Compendio