Skin cancer is the most frequent malignant neoplasm for Caucasian individuals. According to the Skin Cancer Foundation, the incidence of melanoma, the most malignant of skin tumours, and resultant mortality, have increased exponentially during the past 30 years, and continues to grow. [1]. Although often intractable in advanced stages, skin cancer in general and melanoma in particular, if detected in an early stage, can achieve cure ratios of over 95% [1,55]. Early screening of the lesions is, therefore, crucial, if a cure is to be achieved. Most skin lesions classification systems rely on a human expert supported dermatoscopy, which is an enhanced and zoomed photograph of the lesion zone. Nevertheless and although contrary claims exist, as far as is known by the author, classification results are currently rather inaccurate and need to be verified through a laboratory analysis of a piece of the lesion’s tissue. The aim of this research was to design and implement a system that was able to automatically classify skin spots as inoffensive or dangerous, with a small margin of error; if possible, with higher accuracy than the results achieved normally by a human expert and certainly better than any existing automatic system. The system described in this thesis meets these criteria. It is able to capture an unconstrained image of the affected skin area and extract a set of relevant features that may lead to, and be representative of, the four main classification characteristics of skin lesions: Asymmetry; Border; Colour; and Diameter. These relevant features are then evaluated either through a Bayesian statistical process - both a simple k-Nearest Neighbour as well as a Fuzzy k-Nearest Neighbour classifier - a Support Vector Machine and an Artificial Neural Network in order to classify the skin spot as either being a Melanoma or not. The characteristics selected and used through all this work are, to the author’s knowledge, combined in an innovative manner. Rather than simply selecting absolute values from the images characteristics, those numbers were combined into ratios, providing a much greater independence from environment conditions during the process of image capture. Along this work, image gathering became one of the most challenging activities. In fact several of the initially potential sources failed and so, the author had to use all the pictures he could find, namely on the Internet. This limited the test set to 136 images, only. Nevertheless, the process results were excellent. The algorithms developed were implemented into a fully working system which was extensively tested. It gives a correct classification of between 76% and 92% – depending on the percentage of pictures used to train the system. In particular, the system gave no false negatives. This is crucial, since a system which gave false negatives may deter a patient from seeking further treatment with a disastrous outcome. These results are achieved by detecting precise edges for every lesion image, extracting features considered relevant according to the giving different weights to the various extracted features and submitting these values to six classification algorithms – k-Nearest Neighbour, Fuzzy k-Nearest Neighbour, Naïve Bayes, Tree Augmented Naïve Bayes, Support Vector Machine and Multilayer Perceptron - in order to determine the most reliable combined process. Training was carried out in a supervised way – all the lesions were previously classified by an expert on the field before being subject to the scrutiny of the system. The author is convinced that the work presented on this PhD thesis is a valid contribution to the field of skin cancer diagnostics. Albeit its scope is limited – one lesion per image – the results achieved by this arrangement of segmentation, feature extraction and classification algorithms showed this is the right path to achieving a reliable early screening system. If and when, to all these data, values for age, gender and evolution might be used as classification features, the results will, no doubt, become even more accurate, allowing for an improvement in the survival rates of skin cancer patients.

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MSc. (Biochemistry) / GLOBOCAN 2008 Survey reported that 12.7 million cancer cases with 7.6 million cancer deaths occurred with an astonishing 56% of these cases and 64% of these deaths allocated to economically developing countries, such as South Africa. Statistics are alarming concerning cutaneous malignant melanomas (CMM) with the World Health Organisation (WHO) estimating that 132 000 new cases of CMM arise per annum internationally with CMM incidence rates showing an increase of 28% in men and 12% increase in women worldwide; whilst the Cancer Association of South Africa (CANSA) has reported that skin cancer is the most common cancer in South Africa, with an estimated 20 000 new cases being reported per annum. Normal cells progressively transform into malignant tumours by a process that requires sequential acquisition of mutations in a genome damaged by various intrinsic and exogenous incidences resulting in two distinct and functional outcomes: 1) activation and/or expression of unfavourable oncogenes and 2) inactivation of tumour suppressor genes that code for proteins involved in checkpoints to cell proliferation or cell death. Transformation of dendritic melanocytic epidermal skin cells give rise to different types of skin cancers with CMM being predominant with poor prognosis and 90% of all deaths associated with cutaneous type tumours and CMM has been classified as a multifactorial disease where both environmental and genetic factors/mutations interact in concert to contribute to CMM susceptibility. Conceptual progress in the last decade has added two emerging hallmarks showing increased potential in generality to the already six known hallmarks of cancer, namely reprogramming of cellular energy metabolism and evasion of immune destruction by T and B lymphocytes and macrophages, enabled by core hallmark cancer characteristics such as genome instability and tumour-promoting inflammation. The Warburg Effect has been described, in terms of metabolic particularities of cancers, as an increased glucose uptake, via a shift in energy production from oxidative phosphorylation to a glycolytic pathway, with increased extracellular lactate release by tumours resulting in a consequent decrease in pH in the surrounding tissues, even in the presence of oxygen. This effect contributes to proliferation, invasiveness, metastasis and angiogenesis of malignant cells. Thus, chronic and uncontrolled cell proliferation, representing the essence of tumour growth, involves not only deregulatory control of cell proliferation but also a parallel adjustment to energy metabolic pathways in order to fuel cell growth and division. Over the last twenty years, studies have shown that the concept of programmed cell death (PCD), by apoptosis, serves as a natural barrier to cancer development where both the intrinsic and extrinsic apoptotic circuits conclude in the implementation of progressively...

Overexposure to UV (ultraviolet) radiation has been linked to a number of deleterious effects on human health, particularly epidermal malignancies, which consist of both melanoma and non-melanoma skin cancers, basal cell carcinoma and squamous cell carcinoma. In the 1950’s, an epidermal compound known as Urocanic Acid (UCA) was discovered whose trans isoform was shown to display photoprotective effects against UV radiation. Not long after, the cis-UCA isomer was found to act as a mediator of immune suppression, causing UCA to be removed from all cosmetic products on the commercial market, most notably sunscreen. Numerous studies conducted after this finding further corroborated cis-UCA’s immunosuppressive properties, showing evidence for the ability of cis-UCA to inhibit contact hypersensitivity responses, delayed-type hypersensitivity responses, and allograft rejection. Early evidence for a mechanism of action behind cis-UCA’s immunosuppressive properties were widespread, including modulation of antigen-presenting cells, interaction with histamine receptors, and regulation of cytokine expression. The immunosuppressive nature of cis-UCA quickly became associated with an ability to facilitate cancerous progression, particularly regarding epidermal malignancies. Interesting theories were raised about the evolutionary basis for cis-UCA’s immunosuppressive nature, including speculation that cis-UCA was meant to induce immunosuppression following ultraviolet exposure in order to prevent autoimmune responses against sunburned epidermal cells. After the turn of the 20th century, new research continued to facilitate modern day understanding of the role of UCA. Evidence showed that UCA was ultimately derived from filaggrin within the stratum corneum, interacted with key immune effectors including T-lymphocytes and Langerhans cells, and potentially contributed to acidification of the stratum corneum. Despite the negative reputation cis-UCA has received in regards to facilitating skin cancer evasion of the immune system, research has shown that its immunosuppressive effects may allow it to serve as potent anti-inflammatory therapeutic. In regards to skin cancer, targeting of UCA as a therapeutic varies widely. Some have suggested using UCA as a measure of sunscreen efficacy, as an indirect target that when inhibited can reduce tumor growth, and as a biomarker for skin cancer risk. Others have begun developing UCA-based mimics that retain the benefits of UCA, while avoiding any deleterious effects. The role of UCA in non-melanoma and melanoma malignancies is not well understood, making targeting of UCA as a therapeutic challenging. The aim of this paper is to comprehensively review the scientific literature regarding the pre-21st century history of UCA, followed by an in-depth analysis of post-21st century research. The objective is to determine the overall potential of UCA to serve as a therapeutic target for UV-associated health conditions, most notably dermatologic malignancies.

Student Number : 8325808 - M Family Medicine thesis - Faculty of Health Sciences / Childhood protection from the sun affords lifetime protection from skin cancer. This cross sectional descriptive study was conducted on 184 mothers in 4 medical waiting rooms in Gauteng. The purpose of the study was to determine mothers’ knowledge, attitude and behaviour towards sun protection of their children. Data was collected by means of an anonymous, confidential, self-administered questionnaire. There was a significant correlation between personal behaviour of the mother and behaviour of the use of sun protection on their children. The majority of mothers purchase a sunscreen of SPF factor > 15. Knowledge often does not transfer into behaviour, with many parents still believing that a suntan is healthy. Mothers’ attitudes towards sun protection was positive. Knowing someone with skin cancer does not increase the usage of sun protection. Mothers attain their knowledge of sun protection from magazines and television. Mothers felt they would benefit from more information. Sun avoidance methods need to be taught and the perception of a suntan being healthy needs to be changed in the public media.

Organ‐transplant recipients (OTRs) on a new class of immunosuppressants, rapamycin and its analogues, have reduced cutaneous Squamous Cell Carcinomas (cSCCs). Rapamycin, an mTORC1 inhibitor, is also a known autophagy inducer in experimental models. Autophagy, which literally means self‐eating, is a cell survival mechanism but can also lead to cell death. Therefore, the main hypothesis behind this work is that rapamycin prevents epidermal tumourigenesis by either affecting epidermal mTOR regulation of autophagy and/or selectively affecting epidermal AKT isoform activity. Epidermal keratinocytes move from the proliferating basal layer upwards to the granular layers where they terminally differentiate, forming a layer of flattened, anucleate cells or squames of the cornified layer which provides an essential environmental barrier. However, epidermal terminal differentiation, a specialised form of cell death involving organelle degradation, is poorly understood. The work presented in this thesis shows that analysis of the autophagy marker expression profile during foetal epidermal development, indicates autophagy is constitutively active in the terminally differentiating granular layer of epidermis. Therefore, I hypothesize that autophagy is a mechanism of organelle degradation during terminal differentiation of granular layer keratinocytes. In monolayer keratinocytes, activation of terminal differentiation is accompanied by autophagic degradation of nuclear material, nucleophagy. This suggests that constitutive autophagy is a pro‐death mechanism required for terminal differentiation. In cultured keratinocytes and in epidermal cultures, rapamycinmediated mTORC1 inhibition strongly increases AKT1 activity as well as up‐regulates constitutive granular layer autophagy promoting terminal differentiation. Therefore, autophagy is an important fundamental process in keratinocytes which may be the mechanism by which terminally differentiating keratinocytes of the epidermal granular layer degrade their organelles required for barrier formation. This may have implications for the treatment of patients with barrier defects like psoriasis. In immunosuppressed OTRs, rapamycin may promote epidermal autophagy and AKT1 activity adding to its anti‐tumourigenic properties.

Doctor of Philosophy / Department of Psychological Sciences / Laura A. Brannon / Sun exposure, with its link to the development of skin cancer and other health issues, can be a serious health hazard. In particular, those who primarily work outdoors and are consistently exposed to the sun’s rays are at elevated risk for such health problems. Previous research efforts have focused on appealing to these outdoor workers to practice sun protection behaviors, such as using sunscreen, wearing a hat, or wearing items of clothing that reduce the amount of skin exposed to the sun’s rays. In an effort to promote such sun protection behaviors, study 1 used a 3 X 2 between-subjects design to investigate the effects of tailored messaging and the inclusion of content regarding financial consequences of skin cancer on outdoor workers’ intention to practice sun protection behaviors. Results from study 1 suggest that tailored messaging was equally as effective as targeted messaging, with both being more effective than generic messaging. This finding indicates that some degree of personalization is necessary when promoting safe sun practices to outdoor workers, but that tailoring to individuals is unnecessary. Additionally, the inclusion of financial content in messaging resulted in participants having greater intentions to practice sun protection behaviors. In study 2, managers and supervisors of outdoor workers were studied in determining the importance of consequences related to employee well-being and financial consequences for employers when it comes to encouraging sun protection behaviors in their employees. Using a four-level between-subjects intervention, it was found that managers and supervisors who received messages that emphasized the financial consequences of employee sun exposure had greater intentions to encourage sun protection behaviors in their employees than those who received a message focused solely on employee well-being. This finding indicates that employers may be most concerned with financial consequences when it comes to promoting employee health. Together, studies 1 and 2 provide insight into the most effective methods for promoting sun protection for outdoor workers.

Skin cancer incidence is increasing while the rates of other cancers is declining. The purpose of this quantitative study was to determine whether health self-efficacy predicted skin cancer protective behaviors. The theory of health self-efficacy provided the framework for the study. Secondary data were collected from the 2008 and 2014 Health Information National Trends Surveys. The study sample included women 18-34 years of age because this population is especially vulnerable to skin cancer. Results of logistic regression analyses indicated that higher levels of health self-efficacy predicted greater sunscreen use, but higher health self-efficacy levels did not predict avoidance of tanning bed or booth use. No significant changes were found in sunscreen use and tanning bed and booth use between 2008 and 2014. Findings may be used to develop educational programs and medical interventions to decrease the incidence of skin cancer.

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.

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.