Mechanisms of UVA-mutagenesis remain a matter of debate. Earlier described higher rates of mutation formation per pyrimidine dimer with UVA than with UVB and other evidence suggested that a non-pyrimidine dimer-type of DNA damage contributes more to UVA- than to UVB-mutagenesis. However, more recently published data on the spectra of UVA-induced mutations in primary human skin cells and in mice suggest that pyrimidine dimers are the most common type of DNA damage-inducing mutations not only with UVB, but also with UVA. As this rebuts a prominent role of non-dimer type of DNA damage in UVA-mutagenesis, we hypothesized that the higher mutation rate at UVA-induced pyrimidine dimers, as compared to UVB-induced ones, is caused by differences in the way UVA- and UVB-exposed cells process DNA damage. Therefore, we here compared cell cycle regulation, DNA repair, and apoptosis in primary human fibroblasts following UVB- and UVA-irradiation, using the same physiologic and roughly equimutagenic doses (100-300 J m(-2) UVB, 100-300 kJ m(-2) UVA) we have used previously for mutagenesis experiments with the same type of cells. ELISAs for the detection of pyrimidine dimers confirmed that much fewer dimers were formed with these doses of UVA, as compared to UVB. We found that cell cycle arrests (intra-S, G1/S, G2/M), mediated at least in part by activation of p53 and p95, are much more prominent and long-lasting with UVB than with UVA. In contrast, no prominent differences were found between UVA and UVB for other anti-mutagenic cellular responses (DNA repair, apoptosis). Our data suggest that less effective anti-mutagenic cellular responses, in particular different and shorter-lived cell cycle arrests, render pyrimidine dimers induced by UVA more mutagenic than pyrimidine dimers induced by UVB.

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Incidence of subsequent malignant tumor development in 740 patients with primary cutaneous melanoma verified between 2006 and 2010 at the Semmelweis University was studied retrospectively and was compared to data of sex and age matched Hungarian population. The follow-up period was 1499 person-years for the whole group from the diagnosis of index melanoma with an average of 2 years. Standardized incidence rate (SIR) was established as the ratio of observed and expected values. The risk of all subsequent malignancies was 15- and 10-fold higher in males (SIR: 15.42) and in females (SIR: 10.55) with melanoma, than in the general population. The increased cancer risk resulted mainly from the significantly higher skin tumor development: SIR values were 160.39 and 92.64 for additional invasive melanoma and 342.28 and 77.04 for subsequent in situ melanoma in males and females, respectively. Non-melanoma skin cancers also notably contributed to the higher risk, the SIR was elevated in both genders to the same extent (males: 17.12, females: 17.55). The risk was also significantly higher for extracutaneous tumor development like chronic lymphocytic leukemia, colon and kidney cancer (both genders), non-Hodgkin's lymphoma, cervical cancer (females), and bladder carcinoma (males). These data underline the importance of patient education and the necessity of frequent medical follow up, including a close-up dermatological screening of melanoma survivors for further malignancies.

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signals. Topical application of E6005 did not affect mechanical stimulation-evoked nerve activity, suggesting that the inhibitory effects of E6005 are not due to nervous damage or local anaesthetic action.The cutaneous concentration of cAMP was decreased in mice with dermatitis, and topical E6005 application reversed the decreased concentration. PDE4 is expressed in the keratinocytes (16). Thus, it is possible that the activation of PDE4 (a decrease in the cAMP concentration) in the epidermal keratinocytes is responsible for chronic dermatitis-associated itching and that the inhibition of activated PDE4 relieves the itching. The mechanisms of the cAMP-mediated antipruritic effect remain unclear. Protein kinase A inactivates 5-lipoxygenase through the phosphorylation of its Ser 523 residue, leading to a decrease in leukotriene B 4 production (17). Leukotriene B 4 is a potent itch mediator (18) acting on the BLT1 leukotriene B 4 receptor in primary afferents (19). Leukotriene B 4 produced in keratinocytes is involved in spontaneous scratching in mice with dermatitis (5) and proteinase-activated receptor 2-mediated scratching (20). Thus, it is conceivable that an increase in cAMP concentration by E6005 results in the inhibition of increased production of leukotriene B 4 in keratinocytes in dermatitis.Tryptase release from mast cells is increased in the lesioned skin of patients with atopic dermatitis (21) and NC mice with chronic dermatitis (4). PDE4 inhibitors suppress the degranulation of mast cells through the increase in intra-cellular cAMP (22). Inflammatory cells including T cells are increased in the skin of NC mice with dermatitis (23), T-cell cytokines including interleukin-31 are associated with scratching (2,24), and PDE4 inhibitors suppress the activation and cytokine release of these cells (25). Thus, the anti-inflammatory actions may also contribute to the antipruritic effects of E6005. Sensory C-fibres play an important role in spontaneous scratching in NC mice with dermatitis (26). The sensitivity of C-fibres to heat and chemical stimuli are increased or not affected by cAMP (27), and protein kinase A activation reduces TRPV1 channel desensitization (28). Thus, the direct action of E6005 on primary afferents may not play a role in its antipruritic effect.The present study showed that E6005, a novel PDE4 inhibitor, has acute antipruritic activity in chronic dermatitis. Thus, E6005 is expected to be useful for the treatment of pruritic chronic dermatitis including atopic dermatitis. AcknowledgementsThis study was funded by Eisai Co. Ltd. Tokyo, Japan. Author contributionsTA and YK designed experiments, and TA and TY performed experiments. TA and YK wrote the manuscript. Conflict of interestsThe authors do not report any conflict of interest relevant to this study. Supporting InformationAdditional Supporting Information may be found in the online version of this article: Data S1. Methods. Figure S1. Hind-paw scratching following topical application of vehicle for E6005 in mice. Figure S2. E6005 does n...