Pigmented Melanocytes Are Protected Against Ultraviolet-A-Induced Membrane Damage

The dominant skin pigment melanin is believed to protect human skin against several harmful effects of ultraviolet radiation. It is not clear, however, how melanin located inside melanin-producing melanocytes modulates the effect of ultraviolet radiation on melanocytes themselves. We have determined membrane damage in pigmented and unpigmented albino mouse melanocytes after ultraviolet A radiation, which is suspected to induce melanoma. Unpigmented cells were much more susceptible to ultraviolet-A-induced membrane permeability than pigmented cells. Unpigmented cells were also more susceptible to ultraviolet-A-induced lipid peroxidation than strongly pigmented cells. Furthermore, unpigmented cells were much more susceptible to ultraviolet-A-induced depletion of glutathione than pigmented cells. Reduced glutathione is known to be a major antioxidant of unpigmented skin cells such as fibroblasts and keratinocytes. To examine whether or not glutathione is also a major antioxidant in melanocytes, melanocytes were depleted of glutathione by means of buthionine sulfoximine. We found that depletion of glutathione in pigmented melanocytes did not change lipid damage induced by ultraviolet A radiation. In unpigmented melanocytes, however, depletion of glutathione significantly increased lipid damage induced by ultraviolet A radiation. Thus, pigmented melanocytes apparently contain antioxidants more potent than glutathione, protecting them from ultraviolet-A-induced membrane damage

Experimental α-particle radioimmunotherapy of breast cancer using 227Th-labeled p-benzyl-DOTA-trastuzumab

Background The aim of the present study was to explore the biodistribution, normal tissue toxicity, and therapeutic efficacy of the internalizing low-dose rate alpha-particle-emitting radioimmunoconjugate 227Th-trastuzumab in mice with HER2-expressing breast cancer xenografts. Methods Biodistribution of 227Th-trastuzumab and 227Th-rituximab in nude mice bearing SKBR-3 xenografts were determined at different time points after injection. Tumor growth was measured after administration of 227Th-trastuzumab, 227Th-rituximab, cold trastuzumab, and saline. The toxicity of 227Th-trastuzumab was evaluated by measurements of body weight, blood cell, and clinical chemistry parameters, as well as histological examination of tissue specimens. Results The tumor uptake reached peak levels of 34% ID/g (4.6 kBq/g) 3 days after injection of 400 kBq/kg of 227Th-trastuzumab. The absorbed radiation dose to tumor was 2.9 Gy, while it was 2.4 Gy to femur due to uptake of the daughter nuclide 223Ra in bone; the latter already explored in clinical phases I and II trials without serious toxicity. A significant dose-dependent antitumor effect was observed for dosages of 200, 400, and 600 kBq/kg of 227Th-trastuzumab but no effect of 400 and 600 kBq/kg 227Th-rituximab (non-tumor binding). No serious delayed bone marrow or normal organ toxicity was observed, but there was a statistical significant reduction in blood cell parameters for the highest-dose group of 227Th-trastuzumab treatment. Conclusion Internalizing 227Th-trastuzumab therapy was well tolerated and resulted in a dose-dependent inhibition of breast cancer xenograft growth. These results warrant further preclinical studies aiming at a clinical trial in breast cancer patients with metastases to bone

Operator splitting methods for systems of convection-diffusion equations: nonlinear error mechanisms and correction strategies

Authors final draft post-refereeing.Many numerical methods for systems of convection-diffusion equations are based upon an operator splitting formulation, where convective and diffusive forces are accounted for in separate substeps. We describe the nonlinear mechanism of the splitting error in such numerical methods in the onedimensional case, a mechanism that is intimately linked to the local linearizations introduced implicitly in the (hyperbolic) convection steps by the use of an entropy condition. For convection-dominated flows, we demonstrate that operator splitting methods typically generate a numerical widening of viscous fronts, unless the splitting step is of the same magnitude as the diffusion scale. To compensate for the potentially damaging splitting error, we propose a corrected operator splitting (COS) method for general systems of convection-diffusion equations with the ability of correctly resolving the nonlinear balance between the convective and diffusive forces. In particular, COS produces viscous shocks with correct structure also when the splitting step is large. A front tracking method for systems of conservation laws, which in turn relies heavily on a Riemann solver, constitutes an important part of our COS strategy. The proposed COS method is successfully applied to a system modelling two-phase, multicomponent flow in porous media and a triangular system modelling three-phase flow

Bystander effects in UV-induced genomic instability: Antioxidants inhibit delayed mutagenesis induced by ultraviolet A and B radiation

<p>Abstract</p> <p>Background</p> <p>Genomic instability is characteristic of many types of human cancer. Recently, we reported that ultraviolet radiation induced elevated mutation rates and chromosomal instability for many cell generations after ultraviolet irradiation. The increased mutation rates of unstable cells may allow them to accumulate aberrations that subsequently lead to cancer. Ultraviolet A radiation, which primarily acts by oxidative stress, and ultraviolet B radiation, which initially acts by absorption in DNA and direct damage to DNA, both produced genomically unstable cell clones. In this study, we have determined the effect of antioxidants on induction of delayed mutations by ultraviolet radiation. Delayed mutations are indicative of genomic instability.</p> <p>Methods</p> <p>Delayed mutations in the <it>hypoxanthine phosphoribosyl transferase </it>(<it>hprt</it>) gene were detected by incubating the cells in medium selectively killing <it>hprt </it>mutants for 8 days after irradiation, followed by a 5 day period in normal medium before determining mutation frequencies.</p> <p>Results</p> <p>The UVB-induced delayed <it>hprt </it>mutations were strongly inhibited by the antioxidants catalase, reduced glutathione and superoxide dismutase, while only reduced glutathione had a significant effect on UVA-induced delayed mutations. Treatment with antioxidants had only minor effects on early mutation frequenies, except that reduced glutathione decreased the UVB-induced early mutation frequency by 24 %. Incubation with reduced glutathione was shown to significantly increase the intracellular amount of reduced glutathione.</p> <p>Conclusion</p> <p>The strong effects of these antioxidants indicate that genomic instability, which is induced by the fundamentally different ultraviolet A and ultraviolet B radiation, is mediated by reactive oxygen species, including hydrogen peroxide and downstream products. However, cells take up neither catalase nor SOD, while incubation with glutathione resulted in increased intracellular levels of glutathione. Previously, we have shown that ultraviolet induced delayed mutations may be induced via a bystander effect and that this effect is 5-fold higher for UVB radiation than for UVA radiation. Therefore, we propose that the antioxidants inhibit an ultraviolet radiation-induced bystander effect and that the effect is transmitted via the medium and via an internal transfer between cells, like gap junctional intercellular communication, for UVB radiation and only by the latter mechanism for UVA radiation.</p