%0 Journal Article %~ PubMed %A Gordon-Thomson, Clare %A Gupta, Ritu %A Tongkao-On, Wannit %A Ryan, Anthony %A Halliday, Gary M %A Mason, Rebecca S %T 1α,25 Dihydroxyvitamin D(3) enhances cellular defences against UV-induced oxidative and other forms of DNA damage in skin. %B Photochemical & Photobiological Sciences %D 2012 %C United Kingdom %I RSC Publications %V 11 %N 12 %P 1837-1847 %@ 1474-9092 %X %Z FOR Codes: 60699 110306 %0 Journal Article %~ PubMed %A Cai, Hong %A Santiago, Fernando S %A Prado-Lourenco, Leonel %A Wang, Bo %A Patrikakis, Margaret %A Davenport, Miles P %A Maghzal, Ghassan J %A Stocker, Roland %A Parish, Christopher R %A Chong, Beng H %A Lieschke, Graham J %A Wong, Tak-Wah %A Chesterman, Colin N %A Francis, Douglas J %A Moloney, Fergal J %A Barnetson, Ross St C %A Halliday, Gary M %A Khachigian, Levon M %T DNAzyme Targeting c-jun Suppresses Skin Cancer Growth. %B Science Translational Medicine %D 2012 %C United States %I American Association for the Advancement of Scienc %V 4 %N 139 %P 139ra82 %@ 1946-6242 %X Worldwide, one in three cancers is skin-related, with increasing incidence in many populations. Here, we demonstrate the capacity of a DNAzyme-targeting c-jun mRNA, Dz13, to inhibit growth of two common skin cancer types-basal cell and squamous cell carcinomas-in a therapeutic setting with established tumors. Dz13 inhibited tumor growth in both immunodeficient and immunocompetent syngeneic mice and reduced lung nodule formation in a model of metastasis. In addition, Dz13 suppressed neovascularization in tumor-bearing mice and zebrafish and increased apoptosis of tumor cells. Dz13 inhibition of tumor growth, which required an intact catalytic domain, was due in part to the induction of tumor immunity. In a series of good laboratory practice-compliant toxicology studies in cynomolgus monkeys, minipigs, and rodents, the DNAzyme was found to be safe and well tolerated. It also did not interfere in more than 70 physiologically relevant in vitro bioassays, suggesting a reduced propensity for off-target effects. If these findings hold true in clinical trials, Dz13 may provide a safe, effective therapy for human skin cancer. %Z FOR Codes: 111204 110105 %0 Journal Article %~ PubMed %A Sarchio, Seri N E %A Kok, Lai-Fong %A O'Sullivan, Clare %A Halliday, Gary M %A Byrne, Scott N %T Dermal mast cells affect the development of sunlight-induced skin tumours. %B Experimental Dermatology %D 2012 %C United Kingdom %I Wiley-Blackwell Publishing Ltd. %V 21 %N 4 %P 241-248 %@ 1600-0625 %X Ultraviolet (UV) radiation contained in sunlight is considered a major risk in the induction of skin cancer. While mast cells are best known for their role in allergic responses, they have also been shown to play a crucial role in suppressing the anti-tumour immune response following UV exposure. Evidence is now emerging that UV may also trigger mast cell release of cutaneous tissue remodelling and pro-angiogenic factors. In this review, we will focus on the cellular and molecular mechanisms by which UV recruits and then activates mast cells to initiate and promote skin cancer development. %Z FOR Codes: 110709 %0 Journal Article %~ PubMed %A Khachigian, Levon M %A Cai, Hong %A Moloney, Fergal J %A Parish, Christopher R %A Chong, Beng H %A Stocker, Roland %A Barnetson, Ross St C %A Halliday, Gary M %T Destroying c-Jun Messenger: New Insights into Biological Mechanisms of DNAzyme Function. %B Oncotarget %D 2012 %C United States %I Impact Journals LLC %V 3 %N 6 %P 594-595 %@ 1949-2553 %X The study by Cai and co-workers provided novel insights into the mechanism of action of DNAzymes. Dz13 rendered c-jun mRNA unstable, reduced growth factor expression and increased apoptosis in the tumors without apparent induction of oxidative stress. Interestingly, Dz13-mediated tumor decay was more profound in immunocompetent mice syngeneic to the tumor compared with immunocompromised animals. Immunohistological inspection revealed increased immune and inflammatory cells in Dz13-treated tumors in the immunocompetent mice. In addition, Dz13 mediated tumor regression was prevented by the administration of CD4 or CD8 antibodies, which depleted the mice of the respective T cell subsets. Thus, inhibition of tumor growth by a DNAzyme involves the induction of tumor immunity. These findings suggest that c-Jun inhibition in tumors stimulates apoptosis and adaptive immune mechanisms that attack the tumor. Underpinned by a favorable preclinical safety profile, DNAzymes could provide a new treatment option combining both direct and indirect mechanisms to prevent the growth and spread of non-melanoma skin cancer. %Z FOR Codes: 110304 %0 Journal Article %~ PubMed %A Huang, Xiao Xuan %A Scolyer, Richard A %A Abubakar, Askar %A Halliday, Gary M %T Human 8-oxoguanine-DNA glycosylase-1 is downregulated in human basal cell carcinoma. %B Molecular Genetics and Metabolism %D 2012 %C United States %I Academic Press %V 106 %N 1 %P 127-130 %@ 1096-7206 %X Basal cell carcinoma (BCC) is the most common type of skin cancer and is a major public health problem in many Western countries. It usually occurs as a consequence of exposure to ultraviolet radiation (UV) with sunlight. The DNA photolesion 8-oxo-7,8-dihydroguanine (8-oxo-dG) is caused by reactive oxygen species (ROS) produced in response to UVA, UVB, and oxidative metabolism. If this damaged DNA is not repaired prior to cell division, then gene mutations may persist in daughter cells. Human 8-oxoguanine-DNA glycosylase 1 (hOGG1) is the main enzyme that excises 8-oxo-dG from damaged DNA via the base-excision repair pathway. However, the role of hOGG1 in human skin cancer is unknown. In this study, using immunohistochemical staining, we found low hOGG1 protein expression in human BCC compared to overlying epidermis or normal epidermis. We also found higher levels of 8-oxo-dG within the BCC compared to the basal layers of epidermis overlying the BCC lesions (E-BCC). The results suggest that low expression of hOGG1 within BCC results in accumulation of ROS generated 8-oxo-dG due to low levels of DNA repair, thereby implicating hOGG1 in human BCC carcinogenesis. These ROS are likely to be produced by the cancer cells during metabolism, as the BCC nests are too deep for UV to reach. Our data suggests that procedures that increase expression of hOGG1 within BCC, or protect from ROS may be beneficial for reducing progression of BCC. %Z FOR Codes: 111203 %0 Journal Article %~ PubMed %A Halliday, Gary M %A Cadet, Jean %T It's all about position: the basal layer of human epidermis is particularly susceptible to different types of sunlight-induced DNA damage. %B The Journal of Investigative Dermatology %D 2012 %C United Kingdom %I Nature Publishing Group %V 132 %N 2 %P 265-267 %@ 1523-1747 %X In this issue, Tewari et al. show that although UVB most effectively causes cyclobutane pyrimidine dimers (CPDs) at the human epidermal surface, UVA-induced CPDs predominate in the basal layer. Previous studies found higher accumulation of UVA-induced 8-oxo-7,8-dihydro-2''-deoxyguanosine and mutations in the basal layer. Therefore, the epidermal basal layer is particularly sensitive to UVA-induced genetic damage and the formation of mutations. %Z FOR Codes: 110304 %0 Journal Article %~ PubMed %A Thanos, S M %A Halliday, G M %A Damian, D L %T Nicotinamide Reduces Photodynamic Therapy-Induced Immunosuppression In Humans. %B British Journal of Dermatology %D 2012 %C United Kingdom %I Wiley-Blackwell Publishing Ltd. %V 167 %N 3 %P 631-636 %@ 1365-2133 %X Background:??? The immune suppressive effects of topical photodynamic therapy (PDT) are potential contributors to treatment failure after PDT for nonmelanoma skin cancer. Nicotinamide (vitamin B3) prevents immune suppression by ultraviolet radiation, but its effects on PDT-induced immunosuppression are unknown. Objectives:??? We aimed to determine the effects of topical and oral nicotinamide on PDT-induced immunosuppression in humans. Methods:??? Twenty healthy Mantoux-positive volunteers received 5% nicotinamide lotion or vehicle to either side of the back daily for 3 days. Another group of 30 volunteers received 500mg oral nicotinamide or placebo twice daily for 1 week in a randomised, double-blinded, cross-over design. In each study, methyl aminolaevulinate cream was applied to discrete areas on the back, followed by narrowband red light irradiation (37J/cm(2) ) delivered at high (75mW/cm(2) ) or low (15mW/cm(2) ) irradiance rates. Adjacent, unirradiated sites served as controls. Delayed type hypersensitivity (Mantoux) reactions were assessed at treatment and control sites to determine immunosuppression. Results:??? High irradiance rate PDT with vehicle or with placebo caused significant immunosuppression (equivalent to 48% and 50% immunosuppression respectively; both p<0.0001); topical and oral nicotinamide reduced this immunosuppression by 59 and 66% respectively (both p<0.0001). Low irradiance rate PDT was not significantly immunosuppressive in the topical nicotinamide study (15% immunosuppression, NS), but caused 22% immunosuppression in the oral study (placebo arm; p=0.006); nicotinamide reduced this immunosuppression by 69% (p=0.045). Conclusions:??? While the clinical relevance of these findings is currently unknown, nicotinamide may provide an inexpensive means of preventing PDT-induced immune suppression and enhancing PDT cure rates. %Z FOR Codes: 110304 %0 Journal Article %~ PubMed %A Surjana, Devita %A Halliday, Gary M %A Martin, Andrew J %A Moloney, Fergal J %A Damian, Diona L %T Oral nicotinamide reduces actinic keratoses in phase II double-blinded randomized controlled trials. %B Journal of Investigative Dermatology %D 2012 %C United States %I Nature Publishing Group %V 132 %N 5 %P 1497-1500 %@ 1523-1747 %X %Z FOR Codes: 110304 %0 Journal Article %~ PubMed %A Halliday, Gary M %A Zhou, Yue %A Sou, Paul W %A Huang, Xiao X J %A Rana, Sabita %A Bugeja, Matthew J %A Painter, Nicole %A Scolyer, Richard A %A Muchardt, Christian %A Di Girolamo, Nick %A Guy Lyons, J %T The absence of Brm exacerbates photocarcinogenesis. %B Experimental Dermatology %D 2012 %C United Kingdom %I Wiley-Blackwell Publishing Ltd. %V 21 %N 8 %P 599-604 %@ 1600-0625 %X Brm is an ATPase subunit of the SWI/SNF chromatin-remodelling complex. Previously, we identified a novel hotspot mutation in Brm in human skin cancer, which is caused by exposure to ultraviolet radiation (UVR). As SWI/SNF is involved in DNA repair, we investigated whether Brm-/- mice had enhanced photocarcinogenesis. P53+/- and Brm-/-p53+/- mice were also examined as the p53 tumor suppressor gene is mutated early during human skin carcinogenesis. Mice were exposed to a low-dose irradiation protocol that caused few skin tumors in wild-type mice. Brm-/- mice with both p53 alleles intact had an increased incidence of skin and ocular tumors compared to Brm+/+p53+/+ controls. Brm loss in p53+/- mice did not further enhance skin or ocular cancer incidence beyond the increased photocarcinogenesis in p53+/- mice. However, the skin tumors that arose early in Brm-/- p53+/- mice had a higher growth rate. Brm-/- did not prevent UVR-induced apoptotic sunburn cell formation, which is a protective response. Unexpectedly, Brm-/- inhibited UVR-induced immunosuppression, which would be predicted to reduce rather than enhance photocarcinogenesis. In conclusion, the absence of Brm increased skin and ocular photocarcinogenesis. Even when one allele of p53 is lost, Brm has additional tumor suppressing capability. %Z FOR Codes: 110304 %0 Journal Article %~ PubMed %A Cheung, Belamy B %A Koach, Jessica %A Tan, Owen %A Kim, Patrick %A Bell, Jessica L %A D'andreti, Carla %A Sutton, Selina %A Malyukova, Alena %A Sekyere, Eric %A Norris, Murray %A Haber, Michelle %A Kavallaris, Maria %A Cunningham, Anne M %A Proby, Charlotte %A Leigh, Irene %A Wilmott, James S %A Cooper, Caroline L %A Halliday, Gary M %A Scolyer, Richard A %A Marshall, Glenn M %T The retinoid signalling molecule, TRIM16, is repressed during squamous cell carcinoma skin carcinogenesis in vivo and reduces skin cancer cell migration in vitro. %B The Journal of Pathology %D 2012 %C United Kingdom %I John Wiley & Sons Ltd. %V 226 %N 3 %P 451-462 %@ 1096-9896 %X Retinoid therapy is used for chemo-prevention in immuno-suppressed patients at high risk of developing skin cancer. The retinoid signalling molecule, tripartite motif protein 16 (TRIM16), is a regulator of keratinocyte differentiation and a tumour suppressor in retinoid-sensitive neuroblastoma. We sought to determine the role of TRIM16 in skin squamous cell carcinoma (SCC) pathogenesis. We have shown that TRIM16 expression was markedly reduced during the histological progression from normal skin to actinic keratosis and SCC. SCC cell lines exhibited lower cytoplasmic and nuclear TRIM16 expression compared with primary human keratinocyte (PHK) cells due to reduced TRIM16 protein stability. Overexpressed TRIM16 translocated to the nucleus, inducing growth arrest and cell differentiation. In SCC cells, TRIM16 bound to and down regulated nuclear E2F1, this is required for cell replication. Retinoid treatment increased nuclear TRIM16 expression in retinoid-sensitive PHK cells, but not in retinoid-resistant SCC cells. Overexpression of TRIM16 reduced SCC cell migration, which required the C-terminal RET finger protein (RFP)-like domain of TRIM16. The mesenchymal intermediate filament protein, vimentin, was directly bound and down-regulated by TRIM16 and was required for TRIM16-reduced cell migration. Taken together, our data suggest that loss of TRIM16 expression plays an important role in the development of cutaneous SCC and is a determinant of retinoid sensitivity. %Z FOR Codes: 111201 %0 Journal Article %~ PubMed %A Sequeira, Vanessa B %A Rybchyn, Mark S %A Tongkao-On, Wannit %A Gordon-Thomson, Clare %A Malloy, Peter J %A Nemere, Ilka %A Norman, Anthony W %A Reeve, Vivienne E %A Halliday, Gary M %A Feldman, David %A Mason, Rebecca S %T The role of the vitamin D receptor and ERp57 in photoprotection by 1??,25-dihydroxyvitamin D3. %B Molecular Endocrinology %D 2012 %C United States %I The Endocrine Society %V 26 %N 4 %P 574-582 %@ 1944-9917 %X UV radiation (UVR) is essential for formation of vitamin D(3), which can be hydroxylated locally in the skin to 1??,25-dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)]. Recent studies implicate 1,25-(OH)(2)D(3) in reduction of UVR-induced DNA damage, particularly thymine dimers. There is evidence that photoprotection occurs through the steroid nongenomic pathway for 1,25-(OH)(2)D(3) action. In the current study, we tested the involvement of the classical vitamin D receptor (VDR) and the endoplasmic reticulum stress protein 57 (ERp57), in the mechanisms of photoprotection. The protective effects of 1,25-(OH)(2)D(3) against thymine dimers were abolished in fibroblasts from patients with hereditary vitamin D-resistant rickets that expressed no VDR protein, indicating that the VDR is essential for photoprotection. Photoprotection remained in hereditary vitamin D-resistant rickets fibroblasts expressing a VDR with a defective DNA-binding domain or a mutation in helix H1 of the classical ligand-binding domain, both defects resulting in a failure to mediate genomic responses, implicating nongenomic responses for photoprotection. Ab099, a neutralizing antibody to ERp57, and ERp57 small interfering RNA completely blocked protection against thymine dimers in normal fibroblasts. Co-IP studies showed that the VDR and ERp57 interact in nonnuclear extracts of fibroblasts. 1,25-(OH)(2)D(3) up-regulated expression of the tumor suppressor p53 in normal fibroblasts. This up-regulation of p53, however, was observed in all mutant fibroblasts, including those with no VDR, and with Ab099; therefore, VDR and ERp57 are not essential for p53 regulation. The data implicate the VDR and ERp57 as critical components for actions of 1,25-(OH)(2)D(3) against DNA damage, but the VDR does not require normal DNA binding or classical ligand binding to mediate photoprotection. %Z FOR Codes: 110306 %0 Journal Article %~ PubMed %A Halliday, Gary M %A Damian, Diona L %A Rana, Sabita %A Byrne, Scott N %T The suppressive effects of ultraviolet radiation on immunity in the skin and internal organs: Implications for autoimmunity. %B Journal of Dermatological Science %D 2012 %C Ireland %I Elsevier Ireland Ltd %V 66 %N 3 %P 176-182 %@ 1873-569X %X Low doses of sunlight that can be received during normal daily activities suppress immunity in humans. Both ultraviolet (UV) B (290-320nm) and UVA (320-400nm) are immunosuppressive. The wavelength dependence in humans shows distinct non-overlapping immunosuppressive peaks of solar effectiveness centred at 310nm UVB and 370nm UVA. In murine models of systemic immunosuppression low dose UV inhibits expansion of effector T cells in skin-draining lymph nodes, and retention of dermal effector memory CD8T cells at sites of antigen challenge. In addition to suppressing skin immunity, UV inhibits immunity in internal organs, including activation of CD8 T cells and cytotoxic T cell activity in the spleen, and memory T cell activation in the spleen and bone marrow. Neither of the chromophores responsible for UV suppression of skin immunity, DNA damage and urocanic acid, nor reactive oxygen species are involved in regulation of CD8 T cells in internal organs. Thus UVB impedes the activation and cytotoxicity of antigen-specific T cells in internal organs by mechanisms independent of suppression of skin immunity. These deleterious effects of low dose UV on skin immunity are likely to contribute to skin cancer, however UV suppression of immunity in internal organs may protect from autoimmunity. Epidemiological evidence suggests that sunlight protects from some autoimmune diseases directed towards internal organs. As UV suppression of skin and internal organ immunity appear to occur via different mechanisms, it may be possible to protect skin immunity and therefore reduce skin cancer incidence without preventing UV from reducing autoimmunity in internal organs. %Z FOR Codes: 110703 110799 %0 Journal Article %~ PubMed %A Dixon, Katie M %A Norman, Anthony W %A Sequeira, Vanessa B %A Mohan, Ritu %A Rybchyn, Mark S %A Reeve, Vivienne E %A Halliday, Gary M %A Mason, Rebecca S %T 1{alpha},25(OH)2-vitamin D and a non-genomic vitamin D analog inhibit ultraviolet radiation-induced skin carcinogenesis. %B Cancer prevention research (Philadelphia, Pa.) %D 2011 %C United States %I American Association for Cancer Research %V 4 %N 9 %P 1485-94 %@ 1940-6215 %X Exposure to ultraviolet radiation (UVR) can lead to a range of deleterious responses in the skin. An important form of damage is the DNA photolesion cyclobutane pyrimidine dimer (CPD). CPDs can be highly mutagenic if not repaired prior to cell division and can lead to UV-induced immunosuppression, making them potentially carcinogenic. UVR exposure also produces vitamin D, a prehormone. Different shapes of the steroid hormone 1??,25-dihydroxyvitamin D??? [1,25(OH)???D???] can produce biological responses through binding either to its cognate nuclear receptor (VDR) to regulate gene transcription or to the VDR associated with plasma membrane caveolae to produce, via signal transduction, nongenomic physiologic responses. Here, we show that both 1,25(OH)???D??? and 1??,25(OH)???-lumisterol (JN), a conformationally restricted analogue that can generate only nongenomic responses, are effective inhibitors of UV damage in an immunocompetent mouse (Skh:hr1) model susceptible to UV-induced tumors. Both 1,25(OH)???D??? and JN significantly reduced UVR-induced CPD, apoptotic sunburn cells, and immunosuppression. Furthermore, these compounds inhibited skin tumor development, both papillomas and squamous cell carcinomas, in these mice. The observed reduction of these UV-induced effects by 1,25(OH)???D??? and JN suggests a role for these compounds in prevention against skin carcinogenesis. To the best of our knowledge, this is the first comprehensive report of an in vivo long-term biological response generated by chronic dosing with a nongenomic-selective vitamin D steroid. %Z FOR Codes: 111603 %0 Journal Article %~ PubMed %A Damian, D L %A Matthews, Y J %A Phan, T A %A Halliday, G M %T An action spectrum for ultraviolet radiation-induced immunosuppression in humans. %B The British Journal of Dermatology %D 2011 %C United Kingdom %I Wiley-Blackwell Publishing Ltd. %V 164 %N 3 %P 657-659 %@ 1365-2133 %X The immune-suppressive effects of sunlight play a central role in skin carcinogenesis. Ultraviolet (UV) B radiation is highly immunosuppressive even at suberythemal doses, and longwave UVA is now also recognized to cause immunosuppression in humans. The relative contributions of UVA and UVB to immunosuppression by incidental daily sun exposure are, however, unclear. %Z FOR Codes: 110304 %0 Journal Article %~ PubMed %A Bock, V L %A Lyons, J G %A Huang, X X J %A Jones, A M %A McDonald, L A %A Scolyer, R A %A Moloney, F J %A Barnetson, R Stc %A Halliday, G M %T BRM and BRG1 subunits of the SWI/SNF chromatin remodelling complex are downregulated upon progression of benign skin lesions into invasive tumours. %B The British journal of dermatology %D 2011 %C United Kingdom %I Wiley-Blackwell Publishing Ltd. %V 164 %N 6 %P 1221-7 %@ 1365-2133 %X Background??? Nonmelanoma skin cancer is caused by exposure to ultraviolet radiation within sunlight. Actinic keratoses (AKs) are benign precursor lesions that can develop into invasive squamous cell carcinoma (SCC). Little is known about the molecular events that lead to human skin cancer progression from benign to invasive. Objectives??? To determine novel genes that may be involved in skin cancer progression based on data from an initial microarray screen of human skin cancers. Methods??? The SWI/SNF chromatin remodelling ATPase subunit BRM was identified as being downregulated in SCC but not AK compared with normal skin in our microarray screen. Therefore reverse transcription-polymerase chain reaction, gene methylation and protein expression was used to study BRM and its alternative ATPase subunit BRG1 in a range of human skin cancers. Results??? We found reduced levels of mRNA coding for BRM but not BRG1 in SCC. BRM mRNA levels in AK were similar to those in normal skin. Deregulation of BRM did not result from hypermethylation of CpG regions in the promoter of these genes. Both BRM and BRG1 protein was reduced by about 10-fold in 100% of SCC and basal cell carcinoma, but not in AK specimens examined. Conclusions??? BRM protein may be decreased due to low levels of mRNA, while BRG1 protein loss appears to be post-translational. BRM and BRG1 may be novel tumour suppressor genes for human skin cancer. They appear to be involved after development of benign lesions, and are downregulated during progression towards invasion. %Z FOR Codes: 111201 %0 Journal Article %~ PubMed %A Farrell, Andrew W %A Halliday, Gary M %A Lyons, James Guy %T Chromatin Structure Following UV-Induced DNA Damage-Repair or Death? %B International Journal of Molecular Sciences %D 2011 %C Switzerland %I M D P I AG %V 12 %N 11 %P 8063-8085 %@ 1422-0067 %X In eukaryotes, DNA is compacted into a complex structure known as chromatin. The unravelling of DNA is a crucial step in DNA repair, replication, transcription and recombination as this allows access to DNA for these processes. Failure to package DNA into the nucleosome, the individual unit of chromatin, can lead to genomic instability, driving a cell into apoptosis, senescence, or cellular proliferation. Ultraviolet (UV) radiation damage causes destabilisation of chromatin integrity. UV irradiation induces DNA damage such as photolesions and subjects the chromatin to substantial rearrangements, causing the arrest of transcription forks and cell cycle arrest. Highly conserved processes known as nucleotide and base excision repair (NER and BER) then begin to repair these lesions. However, if DNA repair fails, the cell may be forced into apoptosis. The modification of various histones as well as nucleosome remodelling via ATP-dependent chromatin remodelling complexes are required not only to repair these UV-induced DNA lesions, but also for apoptosis signalling. Histone modifications and nucleosome remodelling in response to UV also lead to the recruitment of various repair and pro-apoptotic proteins. Thus, the way in which a cell responds to UV irradiation via these modifications is important in determining its fate. Failure of these DNA damage response steps can lead to cellular proliferation and oncogenic development, causing skin cancer, hence these chromatin changes are critical for a proper response to UV-induced injury. %Z FOR Codes: 110304 %0 Journal Article %~ PubMed %A Javeri, Arash %A Lyons, J Guy %A Huang, Xiao Xuan %A Halliday, Gary M %T Downregulation of cockayne syndrome B protein reduces human 8-oxoguanine DNA glycostlase-1 expression and repair of ultraviolet radiation-induced 8-oxo-7,8-dihydro-2'-deoxyguanine %B Cancer science %D 2011 %C Japan %I Wiley-Blackwell Publishing Japan %V 102 %N 9 %P 1651-8 %@ 1349-7006 %X Human 8-oxoguanine DNA glycosylase-1 (hOGG1) is the key DNA repair enzyme responsible for initiating repair of UV radiation-induced 8-oxo-7,8-dihydro-2''-deoxyguanosine (8-oxo-dG). Previously we have shown that basal cells in human epidermis are particularly sensitive to UVA-mediated DNA damage probably due to low expression of hOGG1. Here we investigate some aspects of the regulatory role of Cockayne syndrome B (CSB) on hOGG1 expression and function. Cockayne syndrome B and hOGG1 genes were knocked down by miRNA technology in the HaCaT human keratinocyte cell line. Loss of the CSB gene decreased hOGG1 mRNA, and loss of hOGG1 increased CSB, indicating that they influence each other''s expression. Protein levels were assessed in cells grown into engineered human skin using immunohistochemistry. This confirmed that CSB knockdown with miRNA reduced hOGG1 protein levels, but hOGG1 knockdown did not influence expression of CSB protein. Using comet assay we found that both hOGG1 and CSB knockdown reduced repair of both UVA- and UVB-induced 8-oxo-dG, consistent with CSB downregulation of hOGG1 mRNA and protein. In contrast, CSB but not hOGG1 knockdown reduced repair of UVB- and UVA-induced cyclobutane pyrimidine dimer photolesions. In engineered human skin, repair of UVA-induced 8-oxo-dG was inhibited by both hOGG1 and CSB knockdown, confirming the functional role of both proteins in cells with 3-D cellular contacts. These findings directly indicate that hOGG1 and CSB influence each other''s expression. CSB is required for maintaining hOGG1 enzyme levels and function. Cockayne syndrome B could therefore be required for 8-oxo-dG repair due to its regulatory effect on hOGG1 expression. Cockayne syndrome B but not hOGG1 is also required for efficient repair of cyclobutane pyrimidine dimers. Cockayne syndrome B regulation of DNA repair could contribute to the effect of UVA in causing mutations that lead to skin cancer in humans. %Z FOR Codes: 110304 %0 Journal Article %~ PubMed %A Frost, Georgia A %A Halliday, Gary M %A Damian, Diona L %T Photodynamic therapy-induced immunosuppression in humans is prevented by reducing the rate of light delivery. %B The Journal of Investigative Dermatology %D 2011 %C United Kingdom, United States %I Nature Publishing Group %V 131 %N 4 %P 962-968 %@ 1523-1747 %X Photodynamic therapy (PDT) of non-melanoma skin cancers currently carries failure rates of 10-40%. The optimal irradiation protocol is as yet unclear. Previous studies showed profound immunosuppression after PDT, which may compromise immune-mediated clearance of these antigenic tumors. Slower irradiation prevents immunosuppression in mice, and may be at least as effective as high-fluence-rate PDT in preliminary clinical trials. The photosensitizers 5-aminolaevulinic acid and/or methyl aminolaevulinate were applied to discrete areas on the backs of healthy Mantoux-positive volunteers, followed by narrowband red light irradiation (632 nm) at varied doses and fluence rates. Delayed type hypersensitivity (Mantoux) reactions were elicited at test sites and control sites to determine immunosuppression. Human ex vivo skin received low- and high-fluence-rate PDT and was stained for oxidative DNA photolesions. PDT caused significant, dose-responsive immunosuppression at high (75 mW cm(-2)) but not low (15 or 45 mW cm(-2)) fluence rates. DNA photolesions, which may be a trigger for immunosuppression, were observed after high-fluence-rate PDT but not when light was delivered more slowly. This study demonstrates that the current clinical PDT protocol (75 mW cm(-2)) is highly immunosuppressive. Simply reducing the rate of irradiation, while maintaining the same light dose, prevented immunosuppression and genetic damage and may have the potential to improve skin cancer outcomes. %Z FOR Codes: 110304 %0 Journal Article %~ PubMed %A Rana, Sabita %A Rogers, Linda Joanne %A Halliday, Gary Mark %T Systemic Low-Dose UVB Inhibits CD8 T Cells and Skin Inflammation by Alternative and Novel Mechanisms. %B The American Journal of Pathology %D 2011 %C United States %I American Society for Investigative Pathology %V 178 %N 6 %P 2783-2791 %@ 0002-9440 %X Exposure to UVB radiation before antigen delivery at an unirradiated site inhibits functional immunological responses. Mice treated dorsally with suberythemal low-dose UVB and immunized with ova in abdominal skin generated ova-specific CD8 T cells with a significantly decreased activation, expansion, and cytotoxic activity compared with unirradiated mice. UVB also impaired the delayed-type hypersensitivity (DTH) reaction to ova. Transfer of CD4(+)CD25(+) cells from UVB-exposed mice did not suppress the ova-specific CD8 T-cell response or DTH reaction in unexposed mice, confirming that systemic low-dose UVB does not induce long-lived functional regulatory CD4(+)CD25(+) T cells. Repairing cyclobutane pyrimidine dimer-type DNA damage and blocking aryl hydrocarbon receptor signaling also did not reverse the immunosuppressive effect of UVB on ova-specific CD8 T cells and DTH, suggesting that cyclobutane pyrimidine dimers and the aryl hydrocarbon receptor are not required in systemic low-dose UVB-induced immunosuppression. The known UVB chromophore, cis-urocanic acid, and reactive oxygen species triggered the inhibition of DTH caused by UVB, but they were not involved in the modulation of CD8 T cells. These findings indicate that systemic low-dose UVB impedes the primary response of antigen-specific CD8 T cells by a novel mechanism that is independent of pathways known to be involved in systemic suppression of DTH. %Z FOR Codes: 110304 %0 Journal Article %~ PubMed %A Norval, Mary %A Halliday, Gary M %T The Consequences of UV-induced Immunosuppression for Human Health. %B Photochemistry and photobiology %D 2011 %C United States %I Wiley-Blackwell Publishing, Inc. %V 87 %N 5 %P 965-77 %@ 1751-1097 %X Exposure to UV radiation can cause suppression of specific immune responses. The pathways leading to the down-regulation are complex, starting from the absorption of UV photons by chromophores in the skin and ending with local and systemic changes in immune mediators, the generation of T and B regulatory cells and inhibition of effector and memory T cell activation. The consequences for human health are thought to be both beneficial and adverse. The former are illustrated by protection against polymorphic light eruption, and possible protection against T cell-mediated autoimmune diseases and asthma. The latter are illustrated by skin cancer, cutaneous lupus erythematosus and infectious diseases including vaccination. Many outstanding questions remain in this rapidly developing and controversial area, not least what advice to give the general public regarding their sun exposure. While considerable advances have been made in the development of strategies that preserve the health benefits of sunlight exposure and decrease its detrimental effects, further research is required before optimal levels of protection are achieved. %Z FOR Codes: 110304 %0 Journal Article %~ PubMed %A Byrne, Scott Napier %A Beaugie, Clare %A O'Sullivan, Clare %A Leighton, Sarah %A Halliday, Gary M %T The Immune-Modulating Cytokine and Endogenous Alarmin Interleukin-33 Is Upregulated in Skin Exposed to Inflammatory UVB Radiation. %B The American Journal of Pathology %D 2011 %C United States %I American Society for Investigative Pathology %V 179 %N 1 %P 211-222 %@ 0002-9440 %X The cellular and molecular mechanisms by which UV radiation modulates inflammation and immunity while simultaneously maintaining skin homeostasis is complex and not completely understood. Similar to the effects of UV, IL-33 has potent immune-modulating properties that are mediated by the downstream induction of cytokines and chemokines. We have discovered that exposure of mice in vivo or human skin samples ex vivo to inflammatory doses of UVB induced IL-33 expression within the epidermal and dermal skin layers. Using a combination of murine cell lines and primary human cells, we demonstrate that both UV and the oxidized lipid platelet activating factor induce IL-33 expression in keratinocytes and dermal fibroblasts. Highlighting the significance of these results, we found that administering IL-33 to mice in vivo suppressed the induction of Th1-mediated contact hypersensitivity responses. This may have consequences for skin cancer growth because UV-induced squamous cell carcinomas that evade immunological destruction were found to express significantly higher levels of IL-33. Finally, we demonstrate that dermal mast cells and skin-infiltrating neutrophils closely associate with UV-induced IL-33-expressing fibroblasts. Our results therefore identify and support a role for IL-33 as an important early danger signal produced in response to inflammation-inducing UV radiation. %Z FOR Codes: 110704 %0 Journal Article %~ PubMed %A Halliday, Gary M %A Byrne, Scott N %A Damian, Diona L %T Ultraviolet a radiation: its role in immunosuppression and carcinogenesis. %B Seminars in Cutaneous Medicine and Surgery %D 2011 %C United States %I W.B. Saunders Co. %V 30 %N 4 %P 214-221 %@ 1558-0768 %X Ultraviolet A (UVA) radiation is immunosuppressive and mutagenic in humans and carcinogenic in animals. UVA suppresses immunity with a bell-shaped dose response. At doses equivalent to 15-20 minutes of sun exposure at noon, UVA contributes to approximately 75% of sunlight-induced immunosuppression. A recent action spectrum, indicating that 360-380 nm but not 320-350 nm UVA suppresses immunity in humans, suggests an important role for reactive oxygen species. UVA also causes an energy crisis in cells, and normalization of adenosine triphosphate with nicotinamide prevents UVA immunosuppression. UVA activation of the alternative complement pathway and defects in memory T-cell development are also involved. Human skin cancers contain mutations in the p53 and BRM genes that are consistent with being induced by UVA. UVA is also mutagenic in human skin equivalents. The basal layer of human skin is more susceptible to UVA-induced mutations than the upper layers. Because skin cancers arise from these basal proliferating cells, this finding is likely to be important and could be attributable to low levels of the DNA repair enzyme OGG1 in basal cells. UVA is therefore likely to make a larger contribution to UVA-induced skin carcinogenesis in humans than is predicted by small animal models as the result of being immunosuppressive and mutagenic for basal keratinocytes. %Z FOR Codes: 111299 110709 110304 %0 Journal Article %~ PubMed %A Matthews, Yasmin J %A Halliday, Gary M %A Phan, Tai A %A Damian, Diona L %T A UVB Wavelength Dependency for Local Suppression of Recall Immunity in Humans Demonstrates a Peak at 300 nm. %B The Journal of investigative dermatology %D 2010 %C United Kingdom, United States %I Nature Publishing Group %V 130 %N 6 %P 1680-4 %@ 1523-1747 %X UVB radiation is a potent environmental carcinogen that not only causes mutations in the skin but also profoundly suppresses skin immune responses. Although this UVB-induced suppression of antitumor immunity has a key role in skin cancer development, the wavelengths within UVB causing greatest in vivo immunosuppression in humans are as yet unknown. We have identified a wavelength dependency for immunosuppression in humans across the UVB spectrum. We established linear dose-response curves for UV-induced local suppression of recall contact hypersensitivity responses at four wavelengths between 289 and 322 nm and found peak immune suppressive effectiveness at 300 nm and no detectable suppression at 322 nm within a physiologically relevant dose range. %Z FOR Codes: 111299 %0 Journal Article %~ PubMed %A Halliday, Gary M %T Common links among the pathways leading to UV-induced immunosuppression. %B The Journal of investigative dermatology %D 2010 %C United Kingdom, United States %I Nature Publishing Group %V 130 %N 5 %P 1209-1212 %@ 1523-1747 %X In this issue, Sreevidya et al. demonstrate unexpected similarities in the downstream events of two molecular triggers of UV-induced immunosuppression. Both platelet-activating factor and cis-urocanic acid produced reactive oxygen species (ROS). Blocking both photoproducts reduced UV-induced genetic damage. Vitamin D, another immunosuppressive photoproduct, does not share this property but instead enhances DNA repair. This study therefore links ROS and genetic damage with two molecular triggers of UV immunosuppression. %Z FOR Codes: 111299 %0 Journal Article %~ PubMed %A Rana, Sabita %A Rogers, Linda J %A Halliday, Gary M %T Immunosuppressive ultraviolet-A radiation inhibits the development of skin memory CD8 T cells. %B Photochemical & Photobiological Sciences %D 2010 %C United Kingdom, It %I Royal Society of Chemistry %V 9 %N 1 %P 25-30 %@ 1474-9092 %X Ultraviolet A (UVA) radiation can have dual affects on the immune system depending on dose. At doses of approximately 1.8 J cm(-2), UVA acts in an immunosuppressive manner, whilst at higher doses UVA can promote recovery and protection against UVB-induced immunosuppression in mice. We utilised a model of contact hypersensitivity (CHS) to investigate how different doses of UVA modulates CD8 T cell immunity against a hapten in vivo. Only 1.8 J cm(-2) UVA decreased the CHS response compared to unirradiated mice, but this did not correlate with an inhibition of primary effector CD8 T cells. A similar expansion of effector CD8 T cells in skin-draining lymph nodes and accumulation of IFN-gamma-producing CD8 T cells in the ear skin was observed between unirradiated and UVA-irradiated mice. However, dermal memory CD8 T cells examined 9 weeks post challenge showed decreased numbers in mice irradiated with 1.8 J cm(-2) UVA compared with unirradiated, 1.3 J cm(-2) and 3.4 J cm(-2) UVA-irradiated mice. Therefore, UVA does not inhibit the expansion, migration or IFN-gamma secretion of CD8 T cells during a primary immune response. However, exposure to immunosuppressive UVA causes a defect in CD8 T cell development that impairs the ability of cells to become long-term memory cells. %Z FOR Codes: 111299 %0 Journal Article %~ PubMed %A Park, Joohong %A Halliday, Gary M %A Surjana, Devita %A Damian, Diona L %T Nicotinamide Prevents Ultraviolet Radiation-induced Cellular Energy Loss. %B Photochemistry and photobiology %D 2010 %C United States %I Wiley-Blackwell Publishing, Inc. %V 86 %N 4 %P 942-8 %@ 1751-1097 %X UV radiation is carcinogenic by causing mutations in the skin and also by suppressing cutaneous antitumor immunity. We previously found nicotinamide (vitamin B3) to be highly effective at reducing UV-induced immunosuppression in human volunteers, with microarray studies on in vivo irradiated human skin suggesting that nicotinamide normalizes subsets of apoptosis, immune function and energy metabolism-related genes that are downregulated by UV exposure. Using human adult low calcium temperature keratinocytes, we further investigated nicotinamide''s effects on cellular energy metabolism. We found that nicotinamide prevented UV-induced cellular ATP loss and protected against UV-induced glycolytic blockade. To determine whether nicotinamide alters the effects of UV-induced oxidative stress posttranslationally, we also measured UV-induced reactive oxygen species (ROS). Nicotinamide had no effect on ROS formation, and at the low UV doses used in these studies, equivalent to ambient daily sun exposure, there was no evidence of apoptosis. Hence, nicotinamide appears to exert its UV protective effects on the skin via its role in cellular energy pathways. %Z FOR Codes: 111201 %0 Journal Article %~ PubMed %A Mason, R S %A Sequeira, V B %A Dixon, K M %A Gordon-Thomson, C %A Pobre, K %A Dilley, A %A Mizwicki, M T %A Norman, A W %A Feldman, D %A Halliday, G M %A Reeve, V E %T PHOTOPROTECTION BY 1alpha,25-DIHYDROXYVITAMIN D AND ANALOGS: FURTHER STUDIES ON MECHANISMS AND IMPLICATIONS FOR UV-DAMAGE. %B The Journal of steroid biochemistry and molecular biology %D 2010 %C United Kingdom %I Pergamon %V 121 %N 1-2 %P 164-8 %@ 1879-1220 %X Ultraviolet (UV) irradiation causes DNA damage in skin cells, immunosuppression and photocarcinogenesis. 1alpha,25-dihydroxyvitamin D3 (1,25D) reduces UV-induced DNA damage in the form of cyclobutane pyrimidine dimers (CPD) in human keratinocytes in culture and in mouse and human skin. UV-induced immunosuppression is also reduced in mice by 1,25D, in part due to the reduction in CPD and a reduction in interleukin (IL-6. The cis-locked analog, 1alpha,25-dihydroxylumisterol3 (JN), which has almost no transactivating activity, reduces UV-induced DNA damage, apoptosis and immunosuppression with similar potency to 1,25D, consistent with a non-genomic signalling mechanism. The mechanism of the reduction in DNA damage in the form of CPD is unclear. 1,25D doubles nuclear expression of p53 compared to UV alone, which suggests that 1,25D facilitates DNA repair. Yet expression of a key DNA repair gene, XPG is not affected by 1,25D. Chemical production of CPD has been described. Incubation of keratinocytes with a nitric oxide donor, SNP, induces CPD in the dark. We previously reported that 1,25D reduced UV-induced nitrite in keratinocytes, similar to aminoguanidine, an inhibitor of nitric oxide synthase. A reduction in reactive nitrogen species has been shown to facilitate DNA repair, but in view of these findings may also reduce CPD formation via a novel mechanism. %Z FOR Codes: 111299 %0 Journal Article %~ PubMed %A Surjana, Devita %A Halliday, Gary M %A Damian, Diona L %T Role of nicotinamide in DNA damage, mutagenesis, and DNA repair. %B Journal of Nucleic Acids %D 2010 %C United States %I Sage - Hindawi Access to Research %V 2010 %N %P 157591 %@ 2090-021X %X Nicotinamide is a water-soluble amide form of niacin (nicotinic acid or vitamin B3). Both niacin and nicotinamide are widely available in plant and animal foods, and niacin can also be endogenously synthesized in the liver from dietary tryptophan. Nicotinamide is also commercially available in vitamin supplements and in a range of cosmetic, hair, and skin preparations. Nicotinamide is the primary precursor of nicotinamide adenine dinucleotide (NAD(+)), an essential coenzyme in ATP production and the sole substrate of the nuclear enzyme poly-ADP-ribose polymerase-1 (PARP-1). Numerous in vitro and in vivo studies have clearly shown that PARP-1 and NAD(+) status influence cellular responses to genotoxicity which can lead to mutagenesis and cancer formation. This paper will examine the role of nicotinamide in the protection from carcinogenesis, DNA repair, and maintenance of genomic stability. %Z FOR Codes: 111201 %0 Journal Article %~ PubMed %A Sou, Paul W %A Delic, Naomi C %A Halliday, Gary M %A Lyons, J Guy %T Snail transcription factors in keratinocytes: enough to make your skin crawl. %B The international journal of biochemistry & cell biology %D 2010 %C United Kingdom %I Pergamon %V 42 %N 12 %P 1940-4 %@ 1357-2725 %X Keratinocytes are the cells in vertebrates that form the frontline barrier to the environment, and are also the most common origin of human cancer. They normally retain tight cell-cell adhesion and low motility, allowing them to terminally differentiate as they stratify. However, they must be able to respond to tissue damage by migrating into and across wounds. This requires reduced mutual adhesion, suppressed terminal differentiation and increased motility, processes driven by the Snail family of transcriptional repressors. The quantity, location and activity of Snail proteins are regulated by growth factors and cytokines to mediate these responses and invoke an inflammatory response. Subversion of these same pathways can promote carcinoma invasion and metastasis. Signaling network facts: ??? Snail1 and Snail2 in keratinocytes are important in promoting migration, inflammation and carcinogenesis, and suppressing terminal differentiation. ??? Extracellular stimuli, including TGFR and EGFR ligands, regulate Snails transcriptionally, via SMAD and MAPK pathways, and post-translationally, by modulating GSK3 and PAK1 activity, which determine Snail stability and intracellular location. ??? Snails directly repress transcription of genes important for cell-cell adhesion and cornified envelope formation. ??? Down-regulation of epithelial cadherins by Snails allows LIMDPs to relocate from adherens junctions to the cytoplasm, where they stimulate MAPK pathways, and to the nucleus, where they bind directly to Snails and act as corepressors. ??? Snail2 is essential for re-epithelialization of healing wounds and can be up-regulated in the keratinocytes at wound margins by p38, ERK1/2 and ERK5 MAPKs, and the arylhydrocarbon receptor. ??? Further information on signaling related to Snail proteins can be found online at KEGG: http://www.genome.jp/kegg-bin/show pathway?hsa04520 http://www.genome.jp/kegg-bin/show_pathway?hsa04350 http://www.genome.jp/kegg-bin/show pathway?hsa04012. %Z FOR Codes: 110304 %0 Journal Article %~ PubMed %A Damian, Diona L %A Kim, Young Jin %A Dixon, Katie M %A Halliday, Gary M %A Javeri, Arash %A Mason, Rebecca S %T Topical calcitriol protects from UV-induced genetic damage but suppresses cutaneous immunity in humans. %B Experimental dermatology %D 2010 %C United Kingdom, Unit %I Wiley-Blackwell Publishing Ltd. %V 19 %N 8 %P e23-30 %@ 1600-0625 %X Calcitriol, the biologically active form of vitamin D, has been reported to cause both suppressive and protective immune effects in mice. Its immune effects in vivo in humans are unclear. We investigated the in vivo effects of topical calcitriol on minimal erythema dose and skin immune responses in healthy volunteers. We found that calcitriol did not protect from ultraviolet (UV)-induced erythema (sunburn) when applied either 24 h before or immediately after irradiation, although it decreased the density of sunburn cells and thymine dimers seen on biopsy when applied 24 h before and again immediately after irradiation. Using the Mantoux reaction as a model of skin immunity, we found that topical calcitriol applied at high total doses reduced the Mantoux responses of nearby untreated, unirradiated skin, suggesting a para-local or systemic immunosuppressive effect not observed with lower calcitriol doses. We then measured UV-induced suppression of Mantoux reactions at vehicle-treated sites and sites treated with low-dose calcitriol, and found that calcitriol neither reduced nor enhanced UV-induced immunosuppression. Despite calcitriol reducing UV-induced DNA damage, which should protect the immune system, it has immunosuppressive effects in our model which may help to explain the efficacy of analogues such as calcipotriol in the treatment of psoriasis. %Z FOR Codes: 111299 %0 Journal Article %~ PubMed %A Damian, Diona L %A Matthews, Yasmin J %A Halliday, Gary M %T Topical riboflavin attenuates ultraviolet B- and ultraviolet A-induced immunosuppression in humans. %B Photodermatology, Photoimmunology & Photomedicine %D 2010 %C United States, Unit %I Wiley-Blackwell Publishing, Inc %V 26 %N 2 %P 66-69 %@ 1600-0781 %X BACKGROUND: Riboflavin (vitamin B(2)) plays a key role in cellular energy metabolism. We have observed previously that nicotinamide (vitamin B(3)), which is also centrally involved in cellular energy restoration after UV irradiation, is highly immune protective in humans. We thus hypothesized that riboflavin might also confer immune protection. METHODS: We irradiated healthy, nickel-allergic volunteers with narrowband UVA (385 nm) and UVB (300 nm) at separate sites on the lower back. These areas were treated with riboflavin solution or vehicle at 24 h and again at 30 min before UV exposure. Forty-eight hours after irradiation, volunteers were patch tested with nickel-containing Finn chambers, at both irradiated and nonirradiated sites, with and without prior riboflavin treatment. The resulting contact hypersensitivity reactions at each site were then measured 72 h later with a reflectance erythema meter in order to determine and compare the immune suppressive effects of each intervention. RESULTS: We observed that low doses of both UVB and longwave UVA1 were immune suppressive in humans. Topical riboflavin conferred immune protection against both wavebands. CONCLUSIONS: Riboflavin is immune protective in humans, and this may reflect the role of the B group vitamins in cellular energy restoration after UV exposure. %Z FOR Codes: 111299 %0 Journal Article %~ PubMed %A Matthews, Yasmin J %A Halliday, Gary M %A Phan, Tai A %A Damian, Diona L %T Wavelength dependency for UVA-induced suppression of recall immunity in humans. %B Journal of dermatological science %D 2010 %C Ireland, Japan %I Elsevier Ireland Ltd %V 59 %N 3 %P 192-7 %@ 1873-569X %X Ultraviolet (UV) A radiation, which has both mutagenic and immune suppressive effects on the skin, is increasingly recognised as a key contributor to cutaneous carcinogenesis. Whilst short wavelength UVB (290-320 nm) is well-recognised as an environmental health hazard, the dangers of UVA (320-400 nm) are relatively unexplored. %Z FOR Codes: 111299 %0 Journal Article %~ PubMed %A Yiasemides, Eleni %A Sivapirabu, Geetha %A Halliday, Gary M %A Park, Joohong %A Damian, Diona L %T Oral nicotinamide protects against ultraviolet radiation-induced immunosuppression in humans. %B Carcinogenesis %D 2009 %C United Kingdom %I Oxford University Press %V 30 %N 1 %P 101-5 %@ 1460-2180 %X Cutaneous immunity, which is a key defence against the development of skin cancers, is suppressed by even small doses of ultraviolet (UV) radiation. Preventing this UV-induced immunosuppression may therefore reduce the incidence of skin cancer. Nicotinamide (vitamin B3) has immune-protective and cancer-preventive effects against UV radiation in mice, and we have shown previously that topical nicotinamide is immune protective in humans. Using the Mantoux model of skin immunity in healthy volunteers, we compared oral nicotinamide to placebo (both administered for 1 week) in a randomized, double-blinded, crossover design against the effects of solar-simulated ultraviolet (ssUV) radiation on delayed-type hypersensitivity to tuberculin purified protein derivative. Discrete areas of the back were irradiated with low doses of ssUV daily for three consecutive days. Immunosuppression, calculated as the difference in Mantoux-induced erythema of irradiated sites compared with unirradiated control sites, was determined in volunteers taking oral nicotinamide and placebo. Significant immunosuppression occurred in an UV dose-dependent manner in the presence of placebo. Oral nicotinamide, at doses of either 1500 or 500 mg daily, was well tolerated and significantly reduced UV immunosuppression with no immune effects in unirradiated skin. Oral nicotinamide is safe and inexpensive and looks promising as a chemopreventive supplement for reducing the immunosuppressive effects of sunlight. %Z FOR Codes: 1112 %0 Journal Article %~ PubMed %A Halliday, Gary M %A Bock, Vanessa L %A Moloney, Fergal J %A Lyons, J Guy %T SWI/SNF: A chromatin-remodelling complex with a role in carcinogenesis. %B The international journal of biochemistry & cell biology %D 2009 %C United Kingdom %I Pergamon %V 41 %N 0 %P 725-8 %@ 1357-2725 %X SWI/SNF is a chromatin-remodelling complex that makes DNA that has been compacted into nucleosomes accessible to transcription factors and repair enzymes. It does this by displacing DNA from the core histone surface. SWI/SNF consists of at least nine subunits, including one of two alternative ATPase subunits, BRM or BRG-1, that provide the energy for remodelling. As it regulates access to DNA it controls many aspects of normal cellular function. Limited studies have recently linked loss of function of SWI/SNF subunits to cancer development, suggesting that it may be a tumor suppressor complex. As epigenetic repression regulates SWI/SNF component expression at least in some cases, restoration of function is therapeutically promising for cancer treatment. Considerably more research is required into deregulation of SWI/SNF in cancer and determination of how this affects tumor development. This is an exciting but poorly understood molecule that may have a role in carcinogenesis. %Z FOR Codes: 111207 111299 %0 Book Section %A Byrne, Scott %A Halliday, Gary %T Sunlight induced immunosuppression: a role for inflammatory mediators in the induction of suppressor cells %B Immunosuppression: New Research %D 2009 %C United States %I Nova Science %V %N %P 185-207 %@ 9781606921029 %E Taylor, Charles B %X %Z FOR Codes: 111299 %0 Book Section %A Halliday, Gary %A Honigsmann, H %T Sunscreens, photoimmunosuppression, and photoaging %B Clinical Guide to Suncreens and Photoprotection %D 2009 %C United States %I Informa Healthcare %V %N %P 101-116 %@ 9781420080858 %E Lim, Henry W %E Draelos, Zoe Kececioglu %X %Z FOR Codes: 111299 110304 %0 Journal Article %~ PubMed %A Stapelberg, Michael P F %A Williams, Rohan B H %A Byrne, Scott N %A Halliday, Gary M %T The Alternative Complement Pathway Seems to be a UVA Sensor that Leads to Systemic Immunosuppression. %B The Journal of investigative dermatology %D 2009 %C United Kingdom, Unit %I Nature Publishing Group %V 129 %N 11 %P 2694-701 %@ 0022-202X %X UV wavebands in sunlight are immunomodulatory. About half the amount of UVA within a minimum erythemal dose of sunlight is systemically immunosuppressive, whereas higher doses protect from UVB immunosuppression in mice. We have earlier shown that these responses to UVA are genetically restricted, as they occur in C57BL/6 but not in Balb/c mice. We used gene set enrichment analysis of microarray data and real-time reverse transcriptase (RT)-PCR confirmation to determine the molecular mechanisms associated with UVA immunomodulation. We found upregulation of mRNA for the alternative complement pathway. The core-enriched genes complement component 3, properdin, and complement factor B were all activated by the immunosuppressive dose of UVA only in UVA-responsive C57BL/6 but not in unresponsive BALB/c mice. This therefore matched the genetic restriction and dose responsiveness of UVA immunosuppression. The immune-protective higher UVA dose prevented UVB from downregulating chemokine receptor 7 and IL-12B, and decreased IL-10, supporting the earlier identification of IL-12 and IL-10 in high-dose UVA protection from UVB immunosuppression. Our study has identified activation of the alternative complement pathway as a trigger of UVA-induced systemic immunosuppression and suggests that this pathway is likely to be an important sensor of UVA-induced damage to the skin. %Z FOR Codes: 110701 111299 %0 Journal Article %~ PubMed %A Sivapirabu, G %A Yiasemides, E %A Halliday, G M %A Park, J %A Damian, D L %T Topical nicotinamide modulates cellular energy metabolism and provides broad-spectrum protection against ultraviolet radiation-induced immunosuppression in humans. %B The British journal of dermatology %D 2009 %C United Kingdom %I Wiley-Blackwell Publishing Ltd. %V 161 %N 6 %P 1357-64 %@ 1365-2133 %X Ultraviolet (UV) radiation can profoundly suppress the cutaneous immune system, thus enhancing carcinogenesis. Agents that prevent UV-induced immunosuppression may thus reduce skin cancer. Nicotinamide (vitamin B3) prevents UV-induced immunosuppression and carcinogenesis in mice, and solar-simulated (ss) UV-induced immunosuppression in humans. Its effectiveness against different UV wavebands and mechanism of action is as yet unknown. %Z FOR Codes: 111299 %0 Journal Article %~ PubMed %A Huang, Xiao Xuan %A Bernerd, Françoise %A Halliday, Gary Mark %T Ultraviolet A within sunlight induces mutations in the epidermal basal layer of engineered human skin. %B The American Journal of Pathology %D 2009 %C United States %I American Society for Investigative Pathology %V 174 %N 4 %P 1534-1543 %@ 1525-2191 %X The ultraviolet B (UVB) waveband within sunlight is an important carcinogen; however, UVA is also likely to be involved. By ascribing mutations to being either UVB or UVA induced, we have previously shown that human skin cancers contain similar numbers of UVB- and UVA-induced mutations, and, importantly, the UVA mutations were at the base of the epidermis of the tumors. To determine whether these mutations occurred in response to UV, we exposed engineered human skin (EHS) to UVA, UVB, or a mixture that resembled sunlight, and then detected mutations by both denaturing high-performance liquid chromatography and DNA sequencing. EHS resembles human skin, modeling differential waveband penetration to the basal, dividing keratinocytes. We administered only four low doses of UV exposure. Both UVA and UVB induced p53 mutations in irradiated EHS, suggesting that sunlight doses that are achievable during normal daily activities are mutagenic. UVA- but not UVB-induced mutations predominated in the basal epidermis that contains dividing keratinocytes and are thought to give rise to skin tumors. These studies indicate that both UVA and UVB at physiological doses are mutagenic to keratinocytes in EHS. %Z FOR Codes: 1112 %0 Journal Article %~ PubMed %A Moloney, Fergal J %A Lyons, J Guy %A Bock, Vanessa L %A Huang, Xiao X %A Bugeja, Matthew J %A Halliday, Gary M %T Hotspot Mutation of Brahma in Non-Melanoma Skin Cancer. %B The Journal of investigative dermatology %D 2008 %C United Kingdom %I Nature Publishing Group %V 129 %N 0 %P 1012-5 %@ 0022-202X %X Mammalian SWItch/sucrose non fermentable (SWI/SNF) remodeling of chromatin modulates transcription and DNA repair. The Brahma (BRM) catalytic subunit of the SWI/SNF complex is one of two mutually exclusive subunits that provide energy for remodeling. BRM has been identified as an important cancer susceptibility locus; however, to date no mutations have been identified in the BRM gene. We performed genetic analysis of BRM in human non-melanoma skin cancers, precancerous lesions, and normal skin revealing a common nonsynonymous point mutation present in one of ten squamous cell and two of six basal cell carcinoma of the skin. This hotspot was not present in germ-line DNA from the same patients, nor in epithelial precancerous lesions. The observed G:C to T:A transversion is typical of mutations occurring following oxidative damage, such as that caused by UVA radiation. This previously unreported hotspot mutation occurs in a highly conserved region of the BRM gene. %Z FOR Codes: 111203 %0 Journal Article %~ PubMed %A Javeri, Arash %A Huang, Xiao Xuan %A Bernerd, Françoise %A Mason, Rebecca S %A Halliday, Gary M %T Human 8-oxoguanine-DNA glycosylase 1 protein and gene are expressed more abundantly in the superficial than basal layer of human epidermis. %B DNA repair %D 2008 %C Netherlands %I Elsevier BV %V 7 %N 9 %P 1542-50 %@ 1568-7864 %X Human 8-oxoguanine-DNA glycosylase 1 (hOGG1) repairs 8-oxo-7,8-dihydro-2''-deoxyguanosine (8-oxo-dG) which results from oxidation of guanine. Reactive oxygen species (ROS) formed in response to ultraviolet (UV) radiation cause this DNA damage, which is involved in pathological processes such as carcinogenesis and aging. The initiation of skin tumors probably requires penetration of UV to the actively dividing basal layer of the epidermis in order for acute damage to become fixed as mutations. Previously, the majority of UVB fingerprint mutations have been found in the upper layers of human skin tumors, while UVA mutations have been found mostly in the lower layer. Our aim was to determine whether this localization of UVA-induced DNA damage is related to stratification of the repair-enzyme hOGG1. Anti-hOGG1 immunohistochemical staining of frozen sections of human foreskin, adult buttock skin, and reconstructed human skin samples showed the highest expression of hOGG1 in the superficial epidermal layer (stratum granulosum). Study of the hOGG1 mRNA expression again showed the highest level in the upper region of the epidermis. This was not regulated by UV irradiation but by the differentiation state of keratinocytes as calcium-induced differentiation increased hOGG1 gene expression. UVA-induced 8-oxo-dG was repaired more rapidly in the upper layer of human skin compared to the lower layers. Our results indicate that weaker expression of the nuclear form of hOGG1 enzyme in the basal cells of the epidermis may lead to a lack of DNA repair in these cells and therefore accumulation of UVA-induced oxidative DNA mutations. %Z FOR Codes: 110304 %0 Journal Article %~ PubMed %A Halliday, Gary M %A Lyons, J Guy %T Inflammatory doses of UV may not be necessary for skin carcinogenesis. %B Photochemistry and Photobiology %D 2008 %C United States %I Wiley-Blackwell Publishing, Inc. %V 84 %N 2 %P 272-283 %@ 0031-8655 %X The UV wavelengths in sunlight are the main cause of skin cancer in humans. Sunlight causes gene mutations, immunosuppression and, at higher doses, inflammation. While it is clear that immunosuppression and gene mutations are essential biologic events via which UV causes skin cancer, the requirement for UV-induced inflammation is less certain. Both the UVB (290-320 nm) and UVA (320-400 nm) wavebands within sunlight can cause skin cancer, gene mutations and immunosuppression. However, UVB, but not UVA, at realistic doses can cause inflammation, and UVB induces skin cancer, immunosuppression and gene mutations at doses much lower than those required to cause inflammation. Inflammation enhances skin carcinogenesis, but may not be UV induced, and inflammatory mediators at doses too low to cause inflammation may be required. UV-induced mutations can cause epidermal cells to make proinflammatory factors or to induce them in the surrounding stroma, creating an oxidizing environment in which additional oncogenic mutations are likely to take place, even in the absence of UV. Our hypothesis is therefore that subinflammatory doses of both UVA and UVB cause benign skin tumors. One of the effects of sunlight-induced mutations may be the production of inflammatory mediators that enhance carcinogenesis. %Z FOR Codes: 110304 111201 %0 Book Section %A Moloney, Fergal %A Halliday, Gary %T Nonmelanoma Skin Cancer %B Clinical and Basic Immunodermatology %D 2008 %C United Kingdom %I Springer-Verlag %V %N %P 223-243 %@ 9781848001640 %E Gaspari, Anthony A. %E Tyring, Stephen K. %X %Z FOR Codes: 110304 110701 %0 Journal Article %~ Isi %A Hersey, P. %A Halliday, G. M. %A Farrelly, M. L. %A DeSilva, C. %A Lett, M. %A Menzies, S. W. %T Phase I/II study of treatment with matured dendritic cells with or without low dose IL-2 in patients with disseminated melanoma %B Cancer Immunology Immunotherapy %D 2008 %C United States %I Springer %V 57 %N 7 %P 1039-1051 %@ 0340-7004 %X %Z FOR Codes: 111204 %0 Journal Article %~ PubMed %A Lyons, J Guy %A Patel, Vyomesh %A Roue, Naomi C %A Fok, Sandra Y %A Soon, Lilian L %A Halliday, Gary M %A Gutkind, J Silvio %T Snail up-regulates proinflammatory mediators and inhibits differentiation in oral keratinocytes. %B Cancer research %D 2008 %C United States %I Software Update ltd. %V 68 %N 12 %P 4525-4530 %@ 1538-7445 %X The transcriptional repressor Snail2 is overexpressed in head and neck squamous cell carcinomas (HNSCC) relative to nonmalignant head and neck mucosal epithelium, and in locally recurrent relative to nonrecurrent HNSCCs. We investigated the mechanisms by which Snails might contribute to the pathogenesis of HNSCCs using cell biological and molecular analyses. Oral keratinocytes that expressed Snails acquired an enhanced ability to attract monocytes and to invade a dense interstitial collagen matrix. They were also found to up-regulate production of proinflammatory cytokines and cyclooxygenase-2 (COX2), which have previously been shown to correlate with malignancy. Induction of nuclear factor-kappaB transcriptional activity by Snails was weak and not sufficient to account for the elevated levels of COX2, interleukin (IL)-6, IL8, or CXCL1. In addition, expression of Snails in oral keratinocytes impaired desquamation in vitro and strongly repressed expression of both ELF3 and matriptase-1, which play important roles in the terminal differentiation of keratinocytes. Reexpression of matriptase-1 in Snail-expressing cells partially rescued desquamation. This implicates Snails as contributing to malignancy both at the early stages, by impeding terminal differentiation, and at later stages, when invasion and inflammation are important. %Z FOR Codes: 110304 111201 %0 Journal Article %~ PubMed %A Byrne, Scott N %A Knox, Matthew C %A Halliday, Gary M %T TGFbeta is responsible for skin tumour infiltration by macrophages enabling the tumours to escape immune destruction. %B Immunology and cell biology %D 2008 %C UK, Australia %I Nature Publishing Group %V 86 %N %P 92-7 %@ 1440-1711 %X Infiltration of skin tumours by macrophages is an important step in tumour progression, although the mechanisms of macrophage recruitment to the tumour mass and the subsequent effects on tumour growth are poorly understood. Transfecting a murine regressing skin tumour with the gene for transforming growth factor (TGF)beta enabled the tumours to grow progressively in vivo thus allowing us to study the role of this cytokine in tumour growth. Flow cytometry was used to show that TGFbeta-mediated tumour progression was accompanied by an increase in tumour-associated macrophages (TAM) and a decrease in tumour-infiltrating dendritic cells (DCs). TAM in TGFbeta-secreting tumours expressed lower levels of major histocompatibility complex II and CD86 compared to DC in control tumours and had a high phagocytic capacity as measured by uptake of latex beads in vivo. Indeed, TGFbeta was directly responsible not only for the enhanced macrophage phagocytosis but also altering the ratio of antigen-presenting cells to favour macrophages over DC. Our results demonstrate that TGFbeta recruitment and retention of macrophages at the tumour site enable effective tumour evasion of the host immune system and reinforces the need to target TGFbeta in human cancer immunotherapy trials. %Z FOR Codes: 1107 %0 Journal Article %A Halliday, Gary %A Norval, M %A Byrne, S N %A Huang, X X %A Wolf, P %T The effects of sunlight on the skin %B Drug Discovery Today: Disease Mechanisms %D 2008 %C United Kingdom %I Elsevier %V 5 %N %P e201-e209 %@ 1740-6765 %X %Z FOR Codes: 111299 %0 Journal Article %~ PubMed %A Rana, Sabita %A Byrne, Scott Napier %A Macdonald, Linda Joanne %A Chan, Carling Yan-Yan %A Halliday, Gary Mark %T Ultraviolet B Suppresses Immunity by Inhibiting Effector and Memory T Cells. %B The American journal of pathology %D 2008 %C United States %I American Society for Investigative Pathology %V 172 %N 4 %P 993-1004 %@ 0002-9440 %X Contact hypersensitivity is a T-cell-mediated response to a hapten. Exposing C57BL/6 mice to UV B radiation systemically suppresses both primary and secondary contact hypersensitivity responses. The effects of UVB on in vivo T-cell responses during UVB-induced immunosuppression are unknown. We show here that UVB exposure, before contact sensitization, inhibits the expansion of effector CD4+ and CD8+ T cells in skin-draining lymph nodes and reduces the number of CD4+ and IFN-gamma+ CD8+ T cells infiltrating challenged ear skin. In the absence of UVB, at 10 weeks after initial hapten exposure, the ear skin of sensitized mice was infiltrated by dermal effector memory CD8+ T cells at the site of challenge. However, if mice were previously exposed to UVB, this cell population was absent, suggesting an impaired development of peripheral memory T cells. This finding occurred in the absence of UVB-induced regulatory CD4+ T cells and did not involve prostaglandin E2, suggesting that the importance of these two factors in mediating or initiating UVB-induced immunosuppression is dependent on UVB dose. Together these data indicate that in vivo T-cell responses are prone to immunoregulation by UVB, including a novel effect on both the activated T-cell pool size and the development of memory T cells in peripheral compartments. %Z FOR Codes: 110704 %0 Journal Article %~ PubMed %A Halliday, Gary M %A Rana, Sabita %T Waveband and dose dependency of sunlight-induced immunomodulation and cellular changes. %B Photochemistry and Photobiology %D 2008 %C United States %I Wiley-Blackwell %V 84 %N 1 %P 35-46 %@ 0031-8655 %X Both the UVB and UVA wavebands within sunlight are immunosuppressive. This article reviews the relationship between wavebands and dose in UV-induced immunosuppression mainly concentrating on responses in humans. It also contrasts the effects of UVB and UVA on cellular changes involved in immunosuppression. Over physiological sunlight doses to which humans can be exposed during routine daily living or recreational pursuits, both UVA and UVB suppress immunity. While there is a linear dose relationship with UVB commencing at doses less than half of what is required to cause sunburn, UVA has a bell-shaped dose response over the range to which humans can be realistically exposed. At doses too low for either waveband to be suppressive, interactions between UVA and UVB augment each other, enabling immunosuppression to occur. At doses beyond where UVA is immunosuppressive, it still contributes to sunlight-induced immunosuppression via this interaction with UVB. While there is little research comparing the mechanisms by which UVB, UVA and their interactions can cause immunosuppression, it is likely that different chromophores and early molecular events are involved. There is evidence that both wavebands disrupt antigen presentation and effect T cell responses. Different individuals are likely to have different immunomodulatory responses to sunlight. %Z FOR Codes: 111299 %0 Journal Article %~ Isi %A Hammond, K %A Chan, C %A Halliday, G %T A characterisation of iNKT cells in mouse skin %B Journal of Investigative Dermatology %D 2007 %C United Kingdom %I Nature Publishing Group %V 127 %N %P 2689-2689 %@ 0022-202X %X %Z FOR Codes: 110304 %0 Journal Article %~ Isi %A Halliday, G %A Phan, T %A Renwick, Y %A Damian, D %T Comparison of the immune suppressive effectiveness of UVB and long-wave UVA in humans %B JOURNAL OF INVESTIGATIVE DERMATOLOGY %D 2007 %C United Kingdom %I Elsevier Ireland Ltd %V 127 %N %P 2690-2690 %@ 0022-202X %X %Z FOR Codes: %0 Journal Article %~ PubMed %A Dixon, K M %A Deo, S S %A Norman, A W %A Bishop, J E %A Halliday, G M %A Reeve, V E %A Mason, R S %T In vivo relevance for photoprotection by the vitamin D rapid response pathway. %B The Journal of steroid biochemistry and molecular biology %D 2007 %C United Kingdom %I Pergamon %V 103 %N 3-5 %P 451-456 %@ 0960-0760 %X Vitamin D is produced by exposure of 7-dehydrocholesterol in the skin to UV irradiation (UVR) and further converted in the skin to the biologically active metabolite, 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) and other compounds. UVR also results in DNA damage producing cyclobutane pyrimidine dimers (CPD). We previously reported that 1,25(OH)(2)D(3) at picomolar concentrations, protects human skin cells from UVR-induced apoptosis, and decreases CPD in surviving cells. 1,25(OH)(2)D(3) has been shown to generate biological responses via two pathways-the classical steroid receptor/genomic pathway or a rapid, non-genomic pathway mediated by a putative membrane receptor. Whether the rapid response pathway is physiologically relevant is unclear. A cis-locked, rapid-acting agonist 1,25(OH)(2)lumisterol(3) (JN), entirely mimicked the actions of 1,25(OH)(2)D(3) to reduce fibroblast and keratinocyte loss and CPD damage after UVR. The effects of 1,25(OH)(2)D(3) were abolished by a rapid-acting antagonist, but not by a genomic antagonist. Skh:hr1 mice exposed to three times the minimal erythemal dose of solar-simulated UVR and treated topically with 1,25(OH)(2)D(3) or JN immediately after UVR showed reduction in UVR-induced UVR-induced sunburn cells (p<0.01 and <0.05, respectively), CPD (p<0.01 for both) and immunosuppression (p<0.001 for both) compared with vehicle-treated mice. These results show for the first time an in vivo biological response mediated by a rapid-acting analog of the vitamin D system. The data support the hypothesis that 1,25(OH)(2)D(3) exerts its photoprotective effects via the rapid pathway and raise the possibility that other D compounds produced in skin may contribute to the photoprotective effects. %Z FOR Codes: 111603 %0 Book Section %A Schwarz, T %A Halliday, Gary %T Photoimmunology %B Photodermatology %D 2007 %C United States %I CRC Press %V %N %P 55-74 %@ 9780849374968 %E Lim, Henry %E Honigsmann, Herbert %E Hawk, John %X %Z FOR Codes: 110799 %0 Book Section %A Halliday, Gary %A Rana, S %T The effects of solar radiation on the immune response in humans %B Biophysical and Physiological Effects of Solar Radiation on Human Skin %D 2007 %C United Kingdom %I Royal Society of Chemistry %V %N %P 127-163 %@ 9781847557957 %E Giacomoni, Paolo U %X %Z FOR Codes: 110799 %0 Journal Article %~ PubMed %A Damian, Diona L %A Patterson, Clare R S %A Stapelberg, Michael %A Park, Joohong %A Barnetson, Ross St C %A Halliday, Gary M %T UV Radiation-Induced Immunosuppression Is Greater in Men and Prevented by Topical Nicotinamide. %B The Journal of investigative dermatology %D 2007 %C United States %I Blackwell Publishing, Inc. %V 128 %N 2 %P 447-54 %@ 0022-202X %X UV radiation-induced immunosuppression augments cutaneous carcinogenesis. The incidence of skin cancer continues to increase despite increased use of sunscreens, which are less effective at preventing immunosuppression than sunburn. Using the Mantoux reaction as a model of skin immunity, we investigated the effects of solar-simulated (ss) UV and its component UVA and UVB wavebands and tested the ability of topical nicotinamide to protect from UV-induced immunosuppression. Healthy, Mantoux-positive volunteers were UV-irradiated on their backs, with 5% nicotinamide or vehicle applied to different sites in a randomized, double-blinded manner. Subsequent Mantoux testing at irradiated and adjacent unirradiated sites enabled measurement of UV-induced immunosuppression with and without nicotinamide. Suberythemal ssUV caused significant immunosuppression, although component UVB and UVA doses delivered independently did not. Men were immunosuppressed by ssUV doses three times lower than those required to immunosuppress women. This may be an important cause of the higher skin cancer incidence and mortality observed in men. Topical nicotinamide prevented immunosuppression, with gene chip microarrays suggesting that the mechanisms of protection may include alterations in complement, energy metabolism and apoptosis pathways. Nicotinamide is a safe and inexpensive compound that could be added to sunscreens or after-sun lotions to improve protection from immunosuppression. immunosuppression.JID JOURNAL CLUB ARTICLE: For questions, answers, and open discussion about this article, please go to http://network.nature.com/group/jidclub %Z FOR Codes: %0 Journal Article %~ PubMed %A Howes, Renae A %A Halliday, Gary M %A Damian, Diona L %T Effect of topical melatonin on ultraviolet radiation-induced suppression of Mantoux reactions in humans. %B Photodermatology, photoimmunology & photomedicine %D 2006 %C Denmark %I Blackwell Munksgaard %V 22 %N 5 %P 267-9 %@ 0905-4383 %X Background: Melatonin, the central neurohormone in circadian rhythm pathways, is recognized to have a variety of immune-enhancing effects. It has previously been shown to reduce ultraviolet (UV) radiation-induced erythema in mice and in humans, but there are as yet no published studies on the effects of melatonin on UV-induced immunosuppression in humans. Methods: We investigated the effects of topical melatonin on solar-simulated (ss) UV-induced suppression of Mantoux reactions in 16 healthy, Mantoux-positive volunteers. Melatonin (5%) and its vehicle were applied in a double-blinded manner to separate areas on the lower back, immediately after each of three consecutive daily ssUV exposures. Various sites on the back received either no irradiation or one of three-graded ssUV doses. Mantoux testing was performed at each site 24 h after the final irradiation, and assessed 72 h later using a reflectance erythema meter. In a separate group of 19 volunteers, the effect of melatonin on minimal erythema dose was assessed both visually and with an erythema meter. Results: We found dose-responsive UV-induced suppression of the Mantoux response in the presence of both vehicle and melatonin; melatonin did not prevent UV-induced immunosuppression in this model. Melatonin was also found to have no effect on the minimal erythema dose. Conclusions: Melatonin conferred no protection against immune suppression or sunburn when applied topically to human skin immediately after irradiation. %Z FOR Codes: 110304 %0 Journal Article %~ PubMed %A Fedorow, H %A Halliday, G M %A Rickert, C H %A Gerlach, M %A Riederer, P %A Double, K L %T Evidence for specific phases in the development of human neuromelanin. %B Neurobiology of aging %D 2006 %C United States %I Elsevier Inc. %V 27 %N 3 %P 506-12 %@ 0197-4580 %X Neuromelanin is a dark-coloured pigment which forms in the dopamine neurons of the human midbrain. The age-related development and regulation of neuromelanin within these dopamine neurons has not been previously described. Optical density and area measurements of unstained neuromelanin in ventral substantia nigra neurons from 29 people spanning the ages of 24 weeks to 95 years old, demonstrated three developmental phases. Neuromelanin was not present at birth and initiation of pigmentation began at approximately 3 years of age, followed by a period of increasing pigment granule number and increasing pigment granule colouration until age 20. In middle and later life the colour of the pigment granules continued to darken but was not associated with any substantial growth in pigment volume. The identification of three phases and changes in the rate of neuromelanin production over time suggests the regulation of neuromelanin production and turnover, possibly through enzymatic processes. %Z FOR Codes: 60105 %0 Journal Article %~ PubMed %A Ooi, T %A Barnetson, R Stc %A Zhuang, L %A McKane, S %A Lee, J H %A Slade, H B %A Halliday, G M %T Imiquimod-induced regression of actinic keratosis is associated with infiltration by T lymphocytes and dendritic cells: a randomized controlled trial. %B The British journal of dermatology %D 2006 %C United Kingdom %I Blackwell Publishing Ltd. %V 154 %N 1 %P 72-8 %@ 0007-0963 %X BACKGROUND: Imiquimod 5% cream is a topically applied immune response modifier that has been shown to give effective treatment of actinic keratosis (AK). The therapeutic effects of imiquimod are likely to involve the provocation of a cutaneous immune response against abnormal cells, an assumption based on a strong correlation between complete clearance rates and the severity of the local skin reactions (erythema, oedema, erosion/ulceration, weeping/exudation and scabbing/crusting); however, no clinical studies have conclusively proved this mechanism. OBJECTIVES: To determine the nature of cellular infiltrates induced by the application of imiquimod to AK lesions and to study cells involved in the cutaneous immune response. METHODS: Eighteen patients participated in this phase I, randomized, double-blind, parallel group, vehicle-controlled study. Enrolled patients were randomized in a 2 : 1 ratio to receive imiquimod cream or vehicle cream and applied study cream to five lesions on the scalp, forearm or upper trunk once daily, three days per week for up to 16 weeks. Each patient had punch biopsies of two distinct AK lesions: a lesion was biopsied before treatment to obtain baseline biomarker levels, and a different lesion was biopsied after 2 weeks of treatment. Biopsy specimens were examined using routine and immunohistochemical staining. RESULTS: The imiquimod group showed statistically significant increases from baseline to week 2 in tissue biomarker levels for CD3, CD4, CD8, CD11c, CD86/CD11c, CD68, HLA-DR and TUNEL. No significant differences were seen for the vehicle group. Complete clearance of all treated AK lesions was achieved in five of 11 (45%) imiquimod patients and in none of six vehicle patients. CONCLUSIONS: Imiquimod stimulates a cutaneous immune response characterized by increases in activated dendritic cells and CD4+ and CD8+ T cells. %Z FOR Codes: %0 Journal Article %~ PubMed %A Russo, P A J %A Halliday, G M %T Inhibition of nitric oxide and reactive oxygen species production improves the ability of a sunscreen to protect from sunburn, immunosuppression and photocarcinogenesis. %B The British journal of dermatology %D 2006 %C UK %I Blackwell Publishing Ltd. %V 155 %N 2 %P 408-15 %@ 0007-0963 %X More effective strategies are required for the prevention of skin cancer, which is caused by ultraviolet (UV) radiation in sunlight. Sunscreens containing UV filters or reflectors offer some protection from sunlight. Pharmacologically active compounds that reduce UV damage offer considerable potential for improving sunscreen formulations. However, few studies have investigated whether the addition of such biological modifiers are an improvement. In this study we supplemented a 2-ethyl hexyl methoxycinnamate-based sunscreen with the nitric oxide (NO) inhibitor N(G)-monomethyl-L-arginine acetate, the iron chelator 2,2''-dipyridyl, which reduces reactive oxygen species (ROS) production, or both. This was to determine whether inhibition of NO, ROS, or both could improve photoprotection by a sunscreen. These sunscreens were compared for photoprotection from sunburn, immunosuppression and skin carcinogenesis in mice. To observe additional photoprotection by the NO and ROS inhibitors, UV doses were used that exceeded the protective capacity of the sunscreen. The combined inhibition of both NO and ROS production, but neither alone, increased sunscreen protection from sunburn and immunosuppression. Similarly, inhibition of both NO and ROS but neither alone reduced tumour multiplicity and incidence, therefore improving sunscreen protection from photocarcinogenesis. Whether NO and ROS inhibition were independently improving sunscreen photoprotection, with both being required for an observable effect, or whether inhibition of an interaction between NO and ROS was responsible for improved photoprotection by the sunscreen is unknown. These studies show that supplementation of a sunscreen with inhibitors of NO and ROS production improves the ability of the sunscreen to protect from sunburn, immunosuppression and photocarcinogenesis. Such an approach may be useful for reducing skin cancer incidence in humans. %Z FOR Codes: 110304 %0 Journal Article %~ PubMed %A Fedorow, H %A Pickford, R %A Kettle, E %A Cartwright, M %A Halliday, G M %A Gerlach, M %A Riederer, P %A Garner, B %A Double, K L %T Investigation of the lipid component of neuromelanin. %B Journal of neural transmission %D 2006 %C Austria %I Springer Wien %V 113 %N 6 %P 735-9 %@ 0300-9564 %X Objective: Neuromelanin (NM) is different to other melanins in that its ultrastructure includes a lipid component. The objectives of this study were to identify and quantify lipids associated with NM. Results: Quantification of the lipid component associated with the pigment on electron micrographs demonstrated that this component comprises 35% of the NM granule volume in the normal brain. The irregular ultrastructural appearance of the NM granules was quite different to the round regular boundary of melanin granules. Using reversed phase high performance liquid chromatography (HPLC) coupled with atmospheric pressure chemical ionization (APCI) mass spectrometry we demonstrated that the isoprenoid dolichol accounted for approximately 12% of total NM pigment mass. Low levels of other lipids were detectable (cholesterol, ubiquinone-10 and alpha-tocopherol) and account for <0.05% of NM lipid, in contrast to cholesterol accounting for 35% of total brain lipids. Conclusion: Unlike other melanins, a substantial proportion of NM volume is comprised of lipid and the major type of lipid associated with NM granules is the isoprenoid dolichol. %Z FOR Codes: 110104 %0 Journal Article %~ PubMed %A Phan, Tai A %A Halliday, Gary M %A Barnetson, Ross Stc %A Damian, Diona L %T Melanin differentially protects from the initiation and progression of threshold UV-induced erythema depending on UV waveband. %B Photodermatology, photoimmunology & photomedicine %D 2006 %C Denmark %I Blackwell Munksgaard %V 22 %N 4 %P 174-80 %@ 0905-4383 %X This study aimed to determine the relationship between various measures of constitutive skin pigmentation and erythema caused by solar-simulated UV (ssUV), 290 and 310 nm UV. Skin pigmentation was assessed clinically by skin typing as well as objectively by measurement of the melanin index (MI) by reflectance spectroscopy. Subjects having Fitzpatrick skin types I-IV were exposed to graded doses of ssUV and either narrowband 310 nm (n=70) or 290 nm (n=69) UV, and assessed 24 h after exposure. Minimal erythema dose (MED) was assessed visually as the lowest dose that caused minimally perceptible erythema. Susceptibility to further development of erythema with higher exposure doses was measured by the gradient of erythema dose-response curves. This was determined by linear regression using reflectance spectrometry data beyond the MED. Although there was considerable variation within each skin type, MI and ssUV MED increased with increasing Fitzpatrick skin type. MI correlated with ssUV MED and 310 nm UV MED, but not 290 nm UV MED. There was also a significant negative correlation between MI and erythema dose-response gradients caused by ssUV, 310 and 290 nm UV. Melanin situated near the basal epidermis may not protect from the initial development of threshold erythema caused by 290 nm UV because it penetrates poorly past the stratum corneum and is not well absorbed by melanin in vivo compared with 310 nm UV. Higher erythemal 290 nm UV doses may reach basal epidermal melanin, which may then afford protection against further 290 nm UV erythema. %Z FOR Codes: %0 Journal Article %~ PubMed %A Gupta, Ritu %A Dixon, Katie M %A Deo, Shivashni S %A Holliday, Carolyn J %A Slater, Michael %A Halliday, Gary M %A Reeve, Vivienne E %A Mason, Rebecca S %T Photoprotection by 1,25 Dihydroxyvitamin D(3) Is Associated with an Increase in p53 and a Decrease in Nitric Oxide Products. %B The Journal of investigative dermatology %D 2006 %C UK, US %I Nature Publishing Group %V 127 %N %P 707-15 %@ 1523-1747 %X Vitamin D is produced in skin by UVB radiation (290-320 nm) acting on 7-dehydrocholesterol. The hypotheses that the active vitamin D hormone, 1,25 dihydroxyvitamin D3 (1,25(OH)2D3), would increase the survival of skin cells after UV irradiation and that surviving cells after 1,25(OH)2D3 treatment would have no increase in DNA damage were tested. The survival of keratinocytes post-UVR was significantly greater after treatment with 1,25(OH)2D3 compared to vehicle (P<0.01). Significant reductions in thymine dimers (TDs) in surviving keratinocytes after UVR were noted in the presence of 1,25(OH)2D3 (P<0.001). Nuclear p53 protein expression increased after UVR and was significantly higher in keratinocytes treated with 1,25(OH)2D3 (P<0.01), whereas NO products were significantly reduced (P<0.05). Both the increase in nuclear accumulation of p53 protein and reduced formation of nitric oxide products may contribute to the reduction in TDs seen with 1,25(OH)2D3 after UVR. Reductions in numbers of sunburn cells (P<0.01) and in TDs (P<0.05) were observed 24 hours after UVR in skin sections from Skh:hr1 mice treated with 1,25(OH)2D3. These results are consistent with the proposal that the vitamin D system in skin may be part of an intrinsic protective mechanism against UV damage. %Z FOR Codes: 111699 %0 Journal Article %~ PubMed %A Phan, Tai A %A Halliday, Gary M %A Barnetson, Ross StC %A Damian, Diona L %T Spectral and dose dependence of ultraviolet radiation-induced immunosuppression. %B Frontiers in bioscience : a journal and virtual library %D 2006 %C United States %I Frontiers in Bioscience %V 11 %N %P 394-411 %@ 1093-4715 %X Ultraviolet radiation (UV) wavelength and dose dependence has been demonstrated for a number of cutaneous endpoints such as erythema, pigment darkening, DNA damage, and photocarcinogenesis. More recently, a number of in-vitro and in-vivo models of UV immunosuppression have implicated UVA (320-400 nm) in immune protection as well as immune suppression. While the wavelength dependencies for immunosuppression within UVB have been well established in mice, the exact role of specific UVA wavelengths has been less clear. Moreover, in humans, the spectral dependence of UV immunosuppression is even less well established. This review firstly outlines the established UV action spectra for a variety of cutaneous effects. The waveband and dose dependence of UV immunosuppression and its mechanisms are explored with a focus on in-vivo models. Finally, since UV immunosuppression along with DNA damage is thought to play a central role in the development of skin cancer, a clearer understanding of the immunosuppressive potential of discrete UV wavebands will allow a more rational approach to our understanding and prevention of skin cancer. %Z FOR Codes: %0 Journal Article %~ PubMed %A Zhang, G %A Luo, X %A Sumithran, E %A Pua, V S C %A Barnetson, R St C %A Halliday, G M %A Khachigian, L M %T Squamous cell carcinoma growth in mice and in culture is regulated by c-Jun and its control of matrix metalloproteinase-2 and -9 expression. %B Oncogene %D 2006 %C United Kingdom %I Nature Publishing Group %V 25 %N %P 7260-6 %@ 0950-9232 %X Squamous cell carcinoma (SCC) is an invasive malignancy of epidermal keratinocytes. Surgical excision is currently the main treatment; however, this can cause scarring and disfigurement. There is accordingly, an acute need for alternative strategies to treat SCC. The transcription factor c-Jun is expressed in human SCC and another common form of invasive skin cancer, basal cell carcinoma together with the mitogenic marker-proliferating cell nuclear antigen. Here, we have employed DNAzymes (catalytic DNA molecules) targeting c-Jun (Dz13) to inhibit c-Jun expression in SCC cells. Dz13 inhibits SCC proliferation and suppresses solid SCC tumor growth and tumor angiogenesis in severe combined immunodeficient mice. We further demonstrate that Dz13 inhibits c-Jun, together with matrix metalloproteinase (MMP)-2 and MMP-9 expression in the tumors, consistent with DNAzyme inhibition of MMP-2 and MMP-9 gelatinolytic activity by zymography. Dz13 also suppressed the expression of vascular endothelial growth factor and fibroblast growth factor-2 in the tumors. These findings demonstrate that c-Jun regulates SCC growth and suggest that DNAzymes targeting this transcription factor may potentially be useful as inhibitors of cutaneous carcinoma. %Z FOR Codes: %0 Journal Article %~ PubMed %A Byrne, Scott N %A Spinks, Nik %A Halliday, Gary M %T The induction of immunity to a protein antigen using an adjuvant is significantly compromised by ultraviolet A radiation. %B Journal of photochemistry and photobiology. B, Biology %D 2006 %C Switzerland %I Elsevier SA %V 84 %N 2 %P 128-34 %@ 1011-1344 %X Ultraviolet (UV) radiation from sunlight causes skin cancer and inhibits priming of the immune system during vaccination. However the dose related effects of the different components of sunlight (UVA and UVB) are complex and require further investigation. Using ovalbumin as a model protein vaccine with saponin as adjuvant we show that both UVA and UVB can suppress the DTH response to a poorly immunogenic protein. Increasing doses of UVB induced increased levels of immunosuppression and tolerance. UVA however, caused a bi-phasic dose response with intermediate but not low or high doses causing primary immunosuppression. No dose of UVA caused significant tolerance. Similar results were observed in both C57BL/6 and Balb/c mice. Our data confirms the complex immunomodulatory dose effects of UVA and UVB for a protein antigen, and shows that both UVB and UVA can suppress immunity induced by a protein with adjuvant. This highlights the importance of considering sun exposure patterns in the future success of both preventing skin cancer development and enhancing vaccination regimes. %Z FOR Codes: 110709 %0 Journal Article %~ PubMed %A Howes, Renae A %A Halliday, Gary M %A Barnetson, Ross Stc %A Friedmann, Adam C %A Damian, Diona L %T Topical capsaicin reduces ultraviolet radiation-induced suppression of Mantoux reactions in humans. %B Journal of Dermatological Science %D 2006 %C Ireland %I Elsevier Ireland Ltd %V 44 %N 2 %P 113-115 %@ 0923-1811 %X %Z FOR Codes: 110304 %0 Journal Article %~ PubMed %A Ishri, Raj K %A Menzies, Scott %A Halliday, Gary M %T Verapamil induces upregulation of P-glycoprotein expression on human monocyte derived dendritic cells. %B Immunological investigations %D 2006 %C United States %I Informa Healthcare %V 35 %N 1 %P 1-18 %@ 0882-0139 %X Overexpression of P-glycoprotein, a transmembrane drug efflux pump that mediates efflux of chemotherapeutic agents contributes to drug resistance in many leukaemia and other cancerous cells. Non-malignant cells including leukocytes also express P-glycoprotein, but physiologic functions for P-glycoprotein are poorly defined. Recently, P-glycoprotein expression has been described in human mononuclear phagocytes and Langerhans cells. It has been shown to play a role in phagocytic cell transmigration through endothelial-lined vessels in an ablumenal-lumenal direction, a process that mimics their migration into lymphatic vessels. Using the monoclonal antibody 4E3, and the P-glycoprotein antagonist, verapamil, the expression of P-glycoprotein on human monocyte-derived dendritic cells was evaluated. Dendritic cells used in this study were CD1a+, CD11c+, CD14-, CD80+, CD83+, CD86+ and MHC-II(High). The expression of these markers increased significantly as the cells matured. P-glycoprotein expression was upregulated as the dendritic cells matured as well as in the presence of the "inflammatory stress" of the pathogenic bacteria Strept. pyogenes. Addition of verapamil or Strept. pyogenes to the culture medium during the final 24 hours significantly upregulated P-glycoprotein expression. Immortalized cell lines did not upregulate P-glycoprotein in the presence of verapamil. Evaluation of other normal cells showed that P-glycoprotein upregulation in the presence of verapamil was also a characteristic of macrophages. This novel observation of the upregulation of P-glycoprotein in the presence of verapamil appears to be a characteristic of activated myeloid derived antigen presenting cells and suggest that P-glycoprotein is essential for these cells as when it is blocked, they respond by increasing expression of this protein. In summary, this work describes that human dendritic cells generated from plastic-adherent monocytes rapidly upregulate expression of P-glycoprotein as they mature, and in the presence of inflammatory stress and the pharmacological agent verapamil, which blocks P-glycoprotein activity, suggesting that P-glycoprotein may play a role in activation as well as in migration of dendritic cells. %Z FOR Codes: 110704 %0 Journal Article %~ PubMed %A Barnetson, Ross Stc %A Ooi, Terry K T %A Zhuang, Liqing %A Halliday, Gary M %A Reid, Catherine M %A Walker, Patrick C %A Humphrey, Stuart M %A Kleinig, Michael J %T [Nle(4)-D-Phe(7)]-alpha-Melanocyte-Stimulating Hormone Significantly Increased Pigmentation and Decreased UV Damage in Fair-Skinned Caucasian Volunteers. %B The Journal of investigative dermatology %D 2006 %C United Kingdom %I Nature Publishing Group %V 126 %N 8 %P 1869-78 %@ 0022-202X %X Epidermal melanin reduces some effects of UV radiation, the major cause of skin cancer. To examine whether induced melanin can provide protection from sunburn injury, 65 subjects completed a trial with the potent synthetic melanotropin, [Nle(4)-D-Phe(7)]-alpha-melanocyte-stimulating hormone ([Nle(4)-D-Phe(7)]-alpha-MSH) delivered by subcutaneous injection into the abdomen at 0.16 mg/kg for three 10-day cycles over 3 months. Melanin density, measured by reflectance spectroscopy, increased significantly in all [Nle(4)-D-Phe(7)]-alpha-MSH-treated subjects. The highest increases were in volunteers with lowest baseline skin melanin levels. In subjects with low minimal erythemal dose (MED) skin type, melanin increased by an average of 41% (from 2.55 to 3.59, P<0.0001 vs placebo) over eight separate skin sites compared with only 12% (from 4.18 to 4.70, P<0.0001 vs placebo) in subjects with a high-MED skin type. Epidermal sunburn cells resulting from exposure to 3 MED of UV radiation were reduced by more than 50% after [Nle(4)-D-Phe(7)]-alpha-MSH treatment in the volunteers with low baseline MED. Thymine dimer formation was also shown to be reduced by 59% (P=0.002) in the epidermal basal layer. This study has shown for the first time the potential ability of a synthetic hormone that augments melanin production to provide photoprotection to people who normally burn in direct sunlight.Journal of Investigative Dermatology (2006) 126, 1869-1878. doi:10.1038/sj.jid.5700317; published online 8 June 2006. %Z FOR Codes: