Indiana University-Purdue University Indianapolis (IUPUI) / Purpose. In the US, melanoma and non-melanoma skin cancer (NMSC) rates have increased substantially in recent decades. While many skin cancer risk factors have been established, the impact of dietary citrus, which is naturally abundant in photocarcinogenic psoralens, remains enigmatic. The purpose of this research was to investigate associations between citrus consumption and risks of melanoma and NMSC, and to conduct a genome-wide study to identify genetic variants that may modify this association. Methods. Participants from the UK Biobank were leveraged for these analyses. Citrus consumption was collected via five rounds of 24-hour recall questionnaires, with complete citrus data available for n=210,126 participants. Ascertainment of melanoma and NMSC cases were identified by international classification of disease codes via linkage with national registries. Logistic regression was used to estimate odds ratios and 95% confidence intervals for the associations between citrus consumption and skin cancer outcomes. Individual citrus products were assessed for independent associations with skin cancer risk, and established skin cancer risk factors were tested for interaction. Joint 2-degree-of-freedom (df) and 1-df tests were used to assess interaction between total citrus consumption and genetic variants. Results. After controlling for covariates, high total citrus consumption was significantly associated with increased melanoma risk, an association primarily driven by orange and orange juice consumption. Skin color was found to be a significant effect modifier for the association between total citrus consumption and melanoma risk, but only before adjusting for multiple comparisons. No significant associations were observed for high total citrus consumption or consumption of any individual citrus products and NMSC risk. Significant associations for half a serving of citrus consumption and NMSC risk were likely due to chance or confounding. Index SNPs on chromosomes 3, 9, and 16 were significant according to the joint 2-df test, and 7 SNPs on chromosome 16 displayed evidence of a citrus-gene interaction. Conclusion. My analyses provide evidence in support of high citrus consumption significantly increasing risk of melanoma, but not NMSC. I also identified SNPs on AFG3L1P that may modify this association. Future research should further explore these associations, particularly for NMSC and to confirm my genetic findings.

Cutaneous melanoma accounts for less than 5% of all skin cancers but over 75% of skin cancer related deaths. Prior biologic research suggests caffeine may arrest cancer cell formation and metastasis in vivo. Additionally, certain tea components exhibit anti-inflammatory, anti-oxidant, and other anti-carcinogenic effects. Prior epidemiologic studies show possible protective effect of both coffee and tea on risk of melanoma, but results remain inconsistent. We examined the association between coffee and tea intake and risk of cutaneous melanoma using the Women’s Health Initiative Observational Study. Coffee and tea intake were measured through self-administered questionnaires. Melanomas were self-reported and physician adjudicated. Cox proportional hazards models were used to evaluate associations. Of the 66,484 white post-menopausal women with no prior history of cancer (average follow up=7.8 years), 73% reported daily intake of coffee, 26% reported daily tea intake, and 398 cases of melanoma were adjudicated. Daily coffee intake (HR=0.84 95% CI=0.66-1.08) and daily tea intake (HR=1.00, 95% CI=0.78-1.29) were not significantly associated with increased risk of cutaneous melanoma compared to non-daily intake. No significant trend was observed with increased daily coffee (p-trend=0.22) or tea intake (p-trend=0.28). In conclusion, we observed insignificant inverse associations between coffee intake and cutaneous melanoma among post-menopausal Caucasian women.

Non melanoma skin cancer (NMSC) is a serious condition caused by chronic ultraviolet (UV) exposure that leads to DNA damage in skin. UV radiation has the potential to lead to DNA damage, which triggers biochemical pathways within a cell. The result is that the cell either undergoes cell cycle arrest, giving the cell time to repair DNA damage, or apoptosis. Sunscreen is the most commonly used treatment for preventing UV induced skin damage, but it involves a number of undesirable and toxic side effects including damaging the dermis, premature aging of skin and underweight child births. This has led to interest in finding safer alternatives to prevent UV damage without the negative side effects of sunscreen. In particular, bovine milk sphingomyelin (SM) is a compound that has the potential to protect against UV damage without any of the dangerous side effects of sunscreen. Here we present the use of SM for UV protection of human keratinocytes (KRTs) to prevent DNA mutations that result from UV exposure. In particular, analysis of the expression of DNA damage biomarkers p21 and p53 was done to determine the potential of SM to prevent DNA damage associated with UV exposure. Both non-SM treated KRTs and KRTs treated with 0.1% SM media 24 hours prior to UV radiation were fixed and IF-stained at 24 hours following 40 mJ/cm2 of UV exposure. Significant differences in both p21 and p53 were observed between the SM treated and non-SM treated cells at the UV dosage level (via t-test; p

No / Metastatic melanoma is the leading cause of skin‑cancer related deaths and while in recent years some progress has been made with targeted therapies, there remains an urgent unmet need for novel therapeutic treatments and reliable diagnostic, prognostic and predictive biomarkers. The emergence of next generation sequencing (NGS) has seen a growing appreciation for the role played by non‑coding genomic transcripts in regulating gene expression and by extension impacting on disease progression. The long non‑coding RNAs (lncRNAs) represent the most enigmatic of these new regulatory molecules. Our understanding of how lncRNAs regulate biological functions and their importance to disease aetiology, while still limited, is rapidly improving, in particular with regards to their role in cancer. Herein we review the identification of several lncRNAs shown to impact on melanoma disease progression and discuss how these molecules are operating at the molecular level.

No description available.

No description available.

No description available.

No description available.

No description available.

Photodynamic therapy (PDT) is a multimodality cancer treatment available for the palliation or eradication of systemic and cutaneous malignancies. In this thesis, the application of PDT is for the treatment of non-melanoma skin cancer (NMSC). While PDT has a well-documented track record, there are, at this time no significant indicators to suggest the superiority of one treatment regime over the next. The motivation for this work is to provide additional evidence pertaining to PDT treatment variables, and to assist in optimising PDT treatment regimes. One such variable is the treatment light dose. Determining the light dose more accurately would assist in optimising treatment schedules. Furthermore, choice of photosensitiser pro-drug type and application times still lack an evidence base. To address issues concerning treatment parameters, fluorescence spectroscopy – a valuable optical diagnostic technique – was used. Monitoring the in vivo PpIX fluorescence and photobleaching during PDT was employed to provide information pertaining to the progression of treatment. This was demonstrated by performing a clinical study at the Photobiology Unit, Ninewells Hospital and Medical School, Dundee. Two different photosensitiser pro-drugs – either 5-aminolaevulinic acid (ALA) or its methyl ester (MAL) – were investigated and based on the fluorescence and pain data recorded both may be equally suitable for topical PDT. During PDT, surface fluorescence is observed to diminish with time – due to photobleaching – although cancerous cells may continue to be destroyed deep down in the tissue. Therefore, it is difficult to ascertain what is happening at depth in the tumour. This raised the questions; How long after surface PpIX fluorescence has diminished is the PDT treatment still effective and to what depths below the surface is effective treatment provided? In order to address these important questions, a three-dimensional (3D) Monte Carlo radiation transfer (MCRT) model was used to compute the light dose and the ¹O₂ production within a tumour, and the PpIX fluorescence emission from the tumour. An implicit dosimetry approach based on a single parameter – fluorescence photobleaching – was used in order to determine the ¹O₂ generation, which is assumed to be related to tissue damage. Findings from our model recommended administering a larger treatment light dose, advocating an increase in the treatment time after surface PpIX fluorescence has diminished. This increase may ultimately assist in optimising PDT treatment regimes, particularly at depth within tumours.