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Background: The nuclear transcription factor c-Jun is preferentially expressed in basal-cell carcinoma. Dz13 is a deoxyribozyme that targets JUN messenger RNA and has inhibited the growth of a range of tumours in mice. We did a phase 1 study to assess safety and tolerability in human beings., Methods: Adults with nodular basal-cell carcinoma were recruited from Royal Prince Alfred Hospital, Sydney, Australia, between September, 2010, and October, 2011. Patients were assigned to receive one intratumoral injected dose of 10, 30, or 100 μg Dz13, in a 50 μL volume of lipid carrier, and were assessed for adverse effects in the first 24 h then at 7, 14, and 28 days after injection. Treated tumours were surgically excised 14 days after injection and compared with the baseline biopsy samples for expression of c-Jun and tumorigenesis markers., Findings: Nine patients were recruited, of whom three received each dose of Dz13. All patients completed the study with no drug-related serious adverse events. No systemic Dz13 exposure was detected. c-Jun expression was reduced in the excised tumours of all nine (100%) patients, compared with baseline, and histological tumour depth had decreased in five (56%) of nine. Proportions of cells positive for caspases 3, 8, and 9 and P53 were increased, but those of cells positive for Bcl-2 and MMP-9 were decreased. Infiltration by inflammatory and immune cells was stimulated., Interpretation: Dz13 was safe and well tolerated after single intratumoral injections at all doses., Funding: Cancer Institute NSW, Cancer Council Australia, and National Health and Medical Research Council., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

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

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, [Nle4-D-Phe7]-alpha-melanocyte-stimulating hormone ([Nle4-D-Phe7]-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 [Nle4-D-Phe7]-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 [Nle4-D-Phe7]-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.

Solar-simulated ultraviolet radiation (ssUV) suppresses immunity in humans. The ultraviolet B (UVB) waveband is recognized as immunosuppressive; however the relative significance of UVA to ssUV immunosuppression is unknown. We created dose and time-response curves for UVB-, UVA-, and ssUV-induced suppression of memory immunity to nickel in humans. UVB caused immunosuppression within 24 h. UVA immunosuppression required 48 h and was normalized by 72 h. UVB alone accounts for ssUV immunosuppression at 24 h, but both UVB and UVA contributed at 48 h. By 72 h neither waveband accounted for ssUV immunosuppression. An interaction between these wavebands was therefore the major contributor. To confirm this dose-response curves were used to determine immune protection factors (IPF) for sunscreens with nickel challenge 72 h following ssUV. A sunscreen with good UVA protection had an IPF twice that of a poor UVA protector, despite providing similar protection from sunburn. Thus UVA was a major contributor to ssUV-induced immunosuppression at 72 h but only with the cooperation of UVB. Hence, UVB initiates immunosuppressive signals within 24 h, followed by UVA at 48 h, then an interaction between UVB and UVA. By 72 h following ssUV exposure, neither UVB nor UVA, but an interaction between them is the major cause of sunlight-induced immunosuppression.

Topical application of NG-methyl-L-arginine and 2,2'-dipyridyl were used to examine the respective roles of nitric oxide and reactive oxygen species in solar-simulated ultraviolet radiation-induced immunosuppression in humans in vivo. Immunosuppression was studied using a nickel contact hypersensitivity recall model. Ultraviolet radiation dose-responses were generated to determine the extent to which NG-methyl-L-arginine and 2,2'-dipyridyl affected the immune response. NG-methyl-L-arginine but not 2,2'-dipyridyl protected the immune system from ultraviolet radiation-induced suppression. Both NG-methyl-L-arginine and 2,2'-dipyridyl inhibited nitrite production. Nitrite is a degradation product of peroxynitrite, a cytotoxic mediator resulting from reactions between nitric oxide and reactive oxygen species. This suggests that nitric oxide, not its downstream product peroxynitrite, was likely to be responsible for solar-simulated ultraviolet radiation-induced immunosuppression. In contrast, both nitric oxide and reactive oxygen species were mediators of solar-simulated ultraviolet radiation-induced apoptosis and loss of dendritic S-100+ cells (probably Langerhans cells) from the epidermis. It is likely that different mechanisms are involved in these ultraviolet-induced endpoints and that events in addition to Langerhans cell depletion are important for local immune suppression to recall antigens in humans. Understanding the mechanisms of cutaneous ultraviolet-induced oxidative stress will assist in the future design of novel products that protect skin from photoaging and skin cancer.

Sunscreens have been advocated as an important means of preventing skin cancer. Ultraviolet radiation induced immunosuppression is recognized as an important event in skin cancer development, yet the effectiveness of sunscreens in protecting the human immune system from ultraviolet radiation (i.e. ultraviolet radiation) is still unclear. The only currently accepted method of sunscreen rating is the sun protection factor system based on the prevention of erythema. We determined immune protection factors for six commercially available sunscreens using a nickel contact hypersensitivity model in humans. Both sun protection factor and immune protection factor testing was performed using the same solar simulated ultraviolet radiation source and dose-responses were used to determine endpoints both with and without sunscreens. We found that the immune protection factor did not correlate with the sun protection factor; however, immune protection factor was significantly correlated to the ultraviolet A protective capability of the sunscreens, indicating that sunscreen protection from ultraviolet A is important for the prevention of ultraviolet immunosuppression, when there is constant ultraviolet B protection. We recommend that sunscreens should be rated against their immune protective capability to provide a better indication of their ability to protect against skin cancer.

Many studies support the role of ultraviolet B in sunlight-induced alteration of the cutaneous immune system. The role of ultraviolet A is less clear, particularly in humans. The aim of this study was to determine the effect of additional ultraviolet A on solar-simulated ultraviolet-induced suppression of recall responses to nickel in humans. Immuno suppression dose-responses were induced in volunteers by exposure to solar-simulated ultraviolet radiation for four consecutive days. The ultraviolet A radiation dose was increased daily by providing additional high-dose ultraviolet A either before, or after the solar-simulated ultraviolet radiation. These ultraviolet A doses can be readily achieved through a sunscreen. Two different ultraviolet A spectra were used; 320-400 nm and 330-400 nm. Ultraviolet A alone did not cause significant immunosuppression, but augmented solar-simulated ultraviolet radiation-induced immunosuppression. Additional ultraviolet A reduced the minimum dose of solar-simulated ultraviolet radiation that was immunosuppressive. Both ultraviolet A spectra had this effect, although photoaugmentation was less pronounced with the 330-400 nm spectrum. Ultraviolet A-induced immediate pigment darkening did not protect from solar-simulated ultraviolet radiation-induced immuno suppression.