Skin cancer is the most widely diagnosed form of cancer and it is split in to non-melanoma skin cancer (NMSC) and cutaneous malignant melanoma (CMM). Cutaneous melanoma has a high propensity for malignancy and it has the highest mortality rate of all skin cancers (de Gruijl, 1999:2004). The first line of treatment for most skin cancers is surgical excision but instances do arise in which surgery is not feasible due to the health of the patient or the location of the lesion. Therefore, viable alternatives are necessary in cases where surgery is not possible (Telfer et al., 2008:36). The skin is readily available for delivery of cytotoxic drugs to treat carcinomas and melanomas so the topical delivery of 5-fluorouracil was investigated in this study. 5-Fluorouracil is a pyrimidine anti-metabolite which interferes with deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) synthesis by inhibiting the nucleotide synthetic enzyme thymidylate synthase (TS) and by becoming misincorporated into RNA and DNA. Thymidylate is essential for replication as well as repair of DNA, in the event of TS inhibition thymidylate is not formed and “thymineless deaths” of cells occur (Chu & Sartorelli, 2009:935; Longley et al., 2003:330). This active pharmaceutical ingredient (API) causes death of atypical and rapidly dividing cells (Tsuji & Karasek, 1986:474). The intravenous and topical routes are approved for 5-fluorouracil and in the case of skin cancer the obvious choice would be topical application (Chu & Sartorelli, 2009:935). Topical application of 5-fluorouracil results in the occurrence of terrible side effects such as severe inflammation, stomatitis, photosensitivity and dermatitis. A reduction in side effects would reduce the stigma associated with topical 5-fluorouracil and in turn increase patient compliance. Topical drug delivery entails the delivery of an API onto or into the various layers of the skin (Flynn & Weiner, 1993:33) in order to treat conditions on or within the skin. Topical application of APIs is non-invasive, painless and simple plus the target site is readily accessible for topical therapy, thus the API is delivered directly to the site of action (Naik et al., 2000:318). In the case of skin cancer, 5-fluorouracil should be able to reach the epidermis because NMSC originates from the keratinocytes (Marks & Hanson, 2010:305) and CMM from melanocytes (de Gruijl, 1999:2004) which are both found in the epidermis. The barrier function of the skin limits the penetration of molecules into the skin and the rate-limiting step is usually penetration into the stratum corneum (Foldvari, 2000:418). The aim of this study was to investigate the diffusion of 5-fluorouracil from formulations into and through the skin. Two physico-chemical properties of 5-fluorouracil that influence skin permeation were determined (aqueous solubility and n-octanol-buffer partition coefficient (log D)). The Pheroid™ drug delivery system was used to enhance the delivery of 5-fluorouracil (Grobler et al., 2008:284). Pheroid™ is a novel technology that is used in the delivery of APIs in pharmaceutical products. It enhances the efficacy of delivered compounds while allowing for the reduction of unwanted adverse effects (Grobler et al., 2008:284). Franz cell skin diffusion studies and tape-stripping were conducted with Pheroid™ and non-Pheroid™ formulations to allow for comparison and determination of the effect of Pheroid™. The in vitro efficacy of 5-fluorouracil in inducing apoptosis of human melanoma cells was investigated using a flow cytometric apoptosis assay. Different concentrations of 5-fluorouracil in formulation were utilised in the experiments so as to observe the cytotoxic effect of 5-fluorouracil. The effect of the drug delivery vehicle on the efficacy of 5-fluorouracil was investigated by utilising API solutions in addition to Pheroid™ and non-Pheroid™ formulations in the experiments. Relatively high concentrations of 5-fluorouracil diffused into and through the skin with Pheroid™ formulations resulting in a greatly enhanced in vitro skin permeation of 5-fluorouracil. The tape-stripping revealed that the Pheroid™ lotions resulted in higher concentrations of 5-fluorouracil in the epidermis and dermis after 12 h as compared to the lotions. There was no deducible trend with respect to the distribution of 5-fluorouracil between the epidermis and dermis. Subsequent to the apoptosis assay it was found that 5-fluorouracil was able to induce apoptosis in A375 cells after a 24 h incubation period. The Pheroid™ treatment of cells resulted in a greater response (mean fluorescence intensity) as compared to treatments with the other drug delivery vehicles at three of the four concentrations. This showed that the drug delivery vehicle played a role in the in vitro efficacy of 5-fluorouracil. Further research must be done in order to combine these results. Optimum and highly effective topical formulations with low doses of 5-fluorouracil must be formulated for the purpose of treating cutaneous cancers with a reduced incidence of side effects. / Thesis (MSc (Pharmaceutics))--North-West University, Potchefstroom Campus, 2013.

Master of Medicine / Non-melanoma skin cancer (NMSC) is the most common human cancer worldwide. Squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) make up almost all NMSC. SCC usually arises from actinic keratosis (AK) as a result of exposure to sunlight. SCC and AK provide a useful clinical model to investigate changes involved in the progression of NMSC. This project examines the expression of Brm, Brg-1, Snail 1 and Snail 2 in the progression of NMSC. Brm and Brg-1 are subunits of the SWI/SNF chromatin-remodelling complex which is involved in regulating the access of cell machinery to DNA by altering the structure of chromatin. It has been suggested that loss of this function is involved in carcinogenesis as the cell is unable to access to DNA normally in order to repair mutations or activate apoptosis. The loss of Brm or Brg-1 has been described in several human cancers. Snail 1 and Snail 2 are zinc-finger transcription factors that are known for their role in epithelial to mesenchymal transition (EMT), a process vital to embryological development. Increased expression of these factors leads to a loss of cell-cell adhesion and a migratory phenotype and has been described in some human cancers. In this project, double-label immunohistochemistry was used to determine the relative expression of these proteins in human SCC, BCC, AK and normal skin. The expression of Snail was unable to be determined due to poor specificity of the antibodies used. The expression of both Brm and Brg-1 proteins was found to be dramatically and consistently decreased in SCC and BCC when compared to normal skin and AK. This loss of Brm and Brg-1 occured as the tumour progressed from benign AK to malignant SCC. This finding suggests that the loss of either Brm or Brg-1 constitutes a key step in carcinogenesis. The results of this study identify Brm and Brg-1 as putative tumour suppressors involved in the progression of non-melanoma skin cancer from benign to malignant.

Source: Dissertation Abstracts International, Volume: 70-03, Section: B, page: 1627. Adviser: Sally W. Vernon. Includes bibliographical references.

Σήμερα ο καρκίνος του δέρματος αποτελεί την πιο κοινή μορφή καρκίνου. Κάθε χρόνο στις ΗΠΑ πάνω απο ένα εκατομμύριο άνθρωποι προσβάλλονται απο κάποια μορφή καρκίνου του δέρματος. Οι τρεις κύριες κατηγορίες δερματικών καρκίνων είναι το Βασικοκυτταρικό καρκίνωμα (BCC), το Ακανθοκυτταρικό καρκίνωμα (SCC) και το Μελάνωμα, με τις δύο πρώτες να αποτελούν πιο ήπιες μορφές καρκίνου με σαφώς καλύτερη πρόγνωση σε σχέση με το μελάνωμα. Ο στόχος αυτής της εργασία είναι να διερευνήσει το ρόλος του μεταγράφικου παράγοντα CREB σε καρκινικά κύτταρα του δέρματος. Ο CREB ρυθμίζει την έκφραση γονιδίων που εμπλέκονται στην επιβίωση, τον πολλαπλασιασμό και το μεταβολισμό της γλουκόζης καθώς και γονίδια που σχετίζονται με τον καρκίνο. ‘Εχει αποδειχθεί οτι ο CREB υπερεκφράζεται ή βρίσκεται στην ενεργή φωσφωριλιωμένη του μορφή σχεδόν σε όλους τους τύπους καρκίνου. Στον καρκίνο του δέρματος υπάρχει ενεργοποίηση και υπερέκφραση του CREB κατά την εξέλιξη προς κακοήθη φαινότυπο. Ξέρουμε επίσης οτι η μεταστατική ικανότητα του μελανώματος σχετίζεται με τη δραστηριότητα και υπερέκφραση του CREB. Παρόλα αυτά η έρευνα σχετικά με τον ρόλο του CREB στον καρκίνο του δέρματος βρίσκεται ακόμα σε πρώιμο στάδιο. Ο στόχος αυτής της ερευνητικής εργασίας είναι να διερευνήσει τον ρόλο του CREB στον καρκίνο του δέρματος και πιο συγκεκριμένα στοχεύουμε να μελετήσουμε την έκφραση του pCREB και του CREB σε δείγματα ασθενών, να εξακριβώσουμε ποιά είναι τα γονίδια-στόχοι του CREB κατά την ογκογένεση και μετάσταση, καθώς και τον αριθμό των αντιτύπων του σε καρκινικές κυτταρικές σειρές και να δημιουργήσουμε stable mutant CREB κυτταρικές σειρές. Τέλος, να μελετήσουμε την επίδραση της αποσιώπησης του CREB σε καρκινικές σειρές με siRNA πειράματα. Αρχικά, πραγματοποιήθηκε μια σειρά απο πειράματα ανοσοïστοχημείας σε Knock out έμβρυα προκειμένου να εντοπίσουμε αντισώματα-δείκτες του πολλαπλασιασμού. Στην συνέχεια μελετήσαμε την παρουσία της ενεργής μορφής του CREB με tissue array σε πλακάκια που έφεραν ιστό από διάφορους τύπους καρκίνου του δέρματος. Επιπλέον, μελετήθηκε η βιωσιμότητα των κυττάρων της καρκινικής σειράς Α 375 ανθρώπινου μελανώματος μετά από την επίδραση της αποσιώπησης της έκφρασης του CREB μέσω siRNA μορίων (CREB siRNA knock down). Τέλος, μελετήθηκε η βιωσιμότητα κυττάρων ανθρώπινου μελανώματος (Α375) που εκφράζουν σταθερά μια dominant negative μορφή του CREB (CREB-M1) και μια σταθερά ενεργοποιημένη μορφή (CREB-FY) σε σχέση με τα κύτταρα ελέγχου που είχαν σταθερά διαμολυνθεί με GFP. / --

Master of Science / Department of Human Nutrition / Weiqun Wang / Exercise has been previously reported to lower cancer risk through reducing circulating IGF-1 and IGF-1-dependent signaling in mouse skin cancer models. This study is to investigate the underlying mechanisms by which exercise might impact IGF-1 pathway regulated by p53 and p53-related proteins in mouse skin epidermis. Female SENCAR mice were pair fed an AIN-93 diet with or without 10-week treadmill exercise at 20 m/min for 60 min daily. Animals were topically treated with TPA or vehicle control 2 hours before sacrifice and the target proteins in the epidermis were assessed by immunohistochemistry and Western blotting. Under TPA or vehicle treatment, MDM2 was significantly reduced in exercised mice compared with sedentary control. Meanwhile, p53 was significantly increased. In addition, p53 transcription target proteins p21, IGFBP-3, and PTEN were elevated in response to exercise. An interaction between exercise and TPA was observed on the decrease of MDM2 and increase of p53, but not p53 down-regulated proteins. Taken together, exercise appears to activate p53 by reducing MDM2 suppression, resulting in enhanced expression of p21, IGFBP-3 and PTEN that might further induce a negative regulation of IGF-1 pathway and therefore contribute to the observed cancer prevention by exercise in this mouse skin cancer model.

Made available in DSpace on 2014-06-11T19:28:27Z (GMT). No. of bitstreams: 0 Previous issue date: 2007-10-15Bitstream added on 2014-06-13T19:16:21Z : No. of bitstreams: 1 silva_ac_me_prud.pdf: 2969033 bytes, checksum: c4389dc81aae218e2c31c85633ce14b2 (MD5) / A radiação ultravioleta (RUV) é considerada o principal agente etiológico no desenvolvimento do câncer de pele. Estudos epidemiológicos apontam para um crescimento mundial de casos novos de câncer cutâneo, superando até mesmo o câncer de pulmão, próstata e mama. Atribui-se esse aumento à degradação do Ozônio estratosférico (O3) e a intensidade da RUV que atinge a superfície terrestre. Diante do exposto, este trabalho pautou-se no estudo da variabilidade temporal do O3, coletado através do sensor TOMS (Total Ozone Mapping Spectrometer) da NASA, para se determinar o grau de influência na intensidade da RUV na região Oeste do Estado de São Paulo. Para análise da variabilidade da RUV, utilizou-se o Índice UV (IUV), que determina a intensidade da RUV na superfície terrestre. Também foi elaborado um Banco de Dados de câncer de pele diagnosticados dentro da área de estudo, para se determinar o perfil epidemiológico dessa enfermidade. Os dados de câncer de pele foram obtidos em três laboratórios que realizam exames anatomopatológicos. Através do método investigativo, por meio de aplicação de questionários, procurou-se também, identificar o comportamento da população em relação aos hábitos de exposição ao sol para se determinar possíveis grupos de risco. Os resultados obtidos mostraram que o O3 apresentou comportamento cíclico em decorrência das estações do ano, com maiores valores na primavera e menores no outono, com média anual em torno de 264 UD. / The longstanding and frequent exposures to the ultraviolet radiation (UVR) are considered the main etiological agent in developing skin cancer. Epidemiological studies point at a global growing in the numbers of new skin cancer cases, even surpassing lung, breast and prostate cancers. It is supposed that the increase in the flux of the photobiologically active radiation is due to the stratospheric ozone (O3) depletion. This work was based upon studying time-spatial variation of the stratospheric O3, using data from TOMS (Total Ozone Mapping Spectrometer) sensor from NASA, in order to determinate the degree of influence of UVR over the western region of São Paulo State, Brazil. To perform an analysis of the UVR variability it was used the UV Index (UVI), a dimensionless parameter, which define the UVR intensity over de earth surface. As contribution to the public polices programs for health, looking for skin cancer prevention, a data bank of new cases of skin cancer was created, with the cases registered in the study area, in order to define the epidemiological profile of this disease. Skin cancer data were extracted from anatomy-pathological biopsies reports collected in three laboratories in Presidente Prudente, SP, Brazil. By means of the investigative method applying questionnaires, it looked for identify the population behavior related to the sun exposure habits in order to determine potential risks groups. Results had shown that stratospheric ozone over the study area presents a cyclic behavior because of the seasons of the year, with higher values in Spring and lower in Fall, with annual average about 264 UD.

Orientador: Jacks Jorge Junior / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba / Made available in DSpace on 2018-08-09T19:45:10Z (GMT). No. of bitstreams: 1 Pulhez_DawtonAbranches_D.pdf: 1061767 bytes, checksum: 2995fbdc5aa9b93180a1ead1803497dd (MD5) Previous issue date: 2007 / Resumo: Os cânceres de pele não-melanoma são os tumores malignos mais freqüentemente encontrados na população brasileira. Dentre estes tipos de tumores encontra-se o carcinoma espinocelular, que também pode estar presente em regiões de mucosa revestidas por epitélio escamoso. Na região bucal, incluindo o lábio inferior, os carcinomas espinocelulares também apresentam altas taxas de incidência e morbidade. O estudo do comportamento biológico dos diversos tipos de cânceres tem sido alvo de numerosos estudos relatados na literatura. Recentemente, estes estudos têm demonstrado o importante papel de enzimas como a ácido graxo sintase (FAS) e de fatores a ela relacionados, como o receptor c-erbB2, o oncogene Skp2 e o gene supressor de tumor p27 durante a proliferação celular e a progressão do câncer. Estas proteínas têm sido consideradas como importantes alvos terapêuticos para o tratamento do câncer. O presente estudo teve como objetivo avaliar a expressão imuno-histoquímica de FAS, c-erbB2, p27 e Skp2 em carcinomas espinocelulares de pele, intra-orais e de lábio inferior, considerando-se que há diferenças no comportamento biológico destes tumores, e contribuindo desta forma para o melhor entendimento destas lesões e do papel biológico destas proteínas durante a progressão do câncer. Os carcinomas intra-orais expressaram os maiores valores para FAS, c-erb-B2 e skp2 e esses valores apresentaram-se diretamente proporcionais entre si nos tumores analisados. Os carcinomas em lábio inferior apresentaram valores de expressão intermediários, enquanto que os maiores valores de p27 foram encontrados nos carcinomas de pele. Estes resultados suportam a tese de que a co-expressão de FAS, c-erb-B2 e skp2 é importante durante a progressão do câncer e desempenha papel contrário ao da expressão da proteína p27. Além disso, essas proteínas são expressadas de forma diferente dentre carcinomas oriundos de diferentes regiões anatômicas e esse comportamento pode influenciar as características clínicas de cada tumor / Abstract: Nonmelanoma skin cancers are the most frequent among Brazil¿s population. Squamous cells carcinoma is among their subtypes and occurs in skin and mucosa. In oral cavity, including lower lip, squamous cells carcinoma is very frequent and shows much damage to the patients. The study of biological behavior of many types of cancer has been used for many researches. Recentely, these researches showed the important role of proteins, like fatty acid synthase (FAS), cerb-B2 receptor, skp2 oncogene and p27 tumor suppressor gene during cellular proliferation and cancer progression. These proteins have been considered important therapeutic aims to cancer treatment. The present study evaluated immunohistochemical expression of FAS, c-erb-B2, p27 and skp2 in oral, lower lip and skin squamous cell carcinomas. Oral carcinomas expressed higher levels of FAS, c-erb-B2 and skp2 and their levels were proportional. Lower lip carcinomas showed intermediary values. The levels of p27 were higher in skin carcinomas. These results support that the co-expression of FAS, c-erb-B2 and skp2 is important in cancer proliferation and has different role of p27 protein. They are different between carcinomas in different regions of the body and their expression may play role in clinical manifestation of tumors / Doutorado / Patologia / Doutor em Estomatopatologia

Mast cells (MCs) are long-lived immune cells, which were reported to play an important role in initiating innate and adaptive immune responses against various infections. MCs accumulate in high numbers in the stroma and at the invasion front of various human cancers, suggesting a possible contribution by MCs to tumour growth. Experimental studies using crosses of MC-deficient Kit-mutant mouse strains with mouse models of epithelial cancers have provided evidence for important MC tumour-promoting functions. However, the complex alterations of the immune system that characterize Kit-mutant mice in addition to their MC deficiency, limit the interpretation of these findings. Numerous key observations made in Kit mutant mice were not reproduced in novel, Kit-independent mouse models of MC deficiency. Thus, the impact of MCs on tumour biology remains unclear. The aim of this study is to clarify the contribution of MCs to the biology of Human papilloma virus (HPV)-induced skin cancer in a Kit-independent mouse model of MC deficiency. In K14-HPV16 transgenic mice, HPV oncogenes are constitutively expressed in the epidermis resulting in epidermal hyperplasia with 100% penetrance and squamous cell carcinoma in about 50% of the animals. A cross to a Kit-mutant line suggested that MCs are important tumour promoters in this model. We crossed K14-HPV16 mice to M5Cre R-DTA line, in which MCs are constitutively depleted with high efficiency and selectivity. Unexpectedly, the loss of MCs neither affected keratinocyte proliferation indices nor altered keratinocyte apoptosis at any stage of HPV-induced neoplasia. Furthermore, the loss of MCs did not result in any detectable changes in composition and gene expression of the inflammatory hematopoietic cell infiltrate in the tumour stroma. This shows that, contrary to current belief, MCs have no important function in orchestrating the tumour micro milieu. In keeping with this finding, MC deficiency resulted in no detectable difference in the incidence growth or grading of SSC in K14-HPV16 transgenic mice. Collectively, these results show that, despite their high density in HPV-induced neoplasia, MC have no role in cancerogenesis or neoplastic progression in the K14-HPV16 mouse model. Our findings also emphasize the importance of novel Kitindependent mouse models in the investigation of MC in vivo functions.

The aims of this DNP project were to evaluate the use of skin cancer preventive behaviors among Hispanic adults within a rural Southwestern Arizona community and to identify the role of self-efficacy expectations and outcome expectations associated with use of skin cancer preventive behaviors within this population. A 42-question survey addressing demographics, skin cancer risk factors, use of skin cancer preventative behaviors, self-efficacy and outcome expectations was developed. The survey was distributed in two primary care clinics in San Luis, Arizona. This survey study included a sample size of 153 Hispanic adults over the age of 18 years old. Findings of this study suggest moderate use of UVR protective behaviors, and minimal use of both CSE and SSE. Use of UVR protective behaviors were associated with skin examination self-efficacy and UVR protection self-efficacy. Results from this project can be used as preliminary data for a prospective intervention study to improve and maintain skin cancer preventive behaviors in Hispanics living in the Southwestern Arizona border area as well as along the entire U.S. –Mexico border. Abbreviations: Advanced Practice Nurse (APN), American Cancer Society (ACS), Clinical Skin Examination (CSE), Doctor of Nursing Practice (DNP), Institutional Board Review (IRB), Nonmelanoma Skin Cancer (NMSC), Primary Investigator (PI), Self-skin examination (SSE), Statistical Package for the Social Science (SPSS), Ultraviolet Radiation (UVR)

University of Macau / Institute of Chinese Medical Sciences