Repair of DNA damage in light sensitive human skin diseases

Summary Repair of UV-light induced DNA damage and changes in the semiconservative DNA synthesis were studied by in vitro autoradiography in the skin of patients with lightdermatoses (polymorphous light eruption, porphyria cutanea tarda, erythropoietic protoporphyria) and xeroderma pigmentosum as well as in that of healthy controls. In polymorphous light eruption the semiconservative DNA replication rate was more intensive in the area of the skin lesions and in the repeated phototest site, the excision repair synthesis appeared to be unaltered. In cutaneous porphyrias a decreased rate of the repair incorporation could be detected. Xeroderma pigmentosum was characterized by a strongly reduced repair synthesis.     

Absence of morphine antagonism of prostaglandin E1-stimulated [3H]3',5'-cyclic adenosine monophosphate accumulation in a rat brain mince system.

Prostaglandin E1 (PGE1)-stimulated [3H]3',5'-cyclic adenosine monophosphate ([3H]cAMP) accumulation was studied in a rat brain mince system to determine if stimulation of net [3H]cAMP accumulation could be prevented or reversed by morphine. Incubated minces of whole brain minus cerebellum were prepared from naive, acutely morphine-treated, and morphine-tolerant and withdrawing rats. Basal levels of [3H]cAMP accumulation in the three groups were equal within experimental limits. Morphine addition to the PGE1-stimulated minces did not prevent or reverse stimulation of [3H]cAMP accumulation in any of the three experimental groups. The data do not support the thesis that PGE1-stimulated cAMP accumulation in brain is a locus of opiate action in the phenomena of opiate analgesia, tolerance, and dependence.     

Effect of cortisone and X-irradiation on cellular depletion and regeneration in the thymus of mice: experimental discrimination between thymus lymphocyte precursors in the bone marrow and in the thymus.

The effect of cortisone treatment on the ability of bone marrow cells to repopulate X-irradiated thymus was investigated. In one experimental series, groups of mice were treated first with cortisone and then irradiated with or without bone marrow protection. Mice treated with either cortisone or radiation alone served as controls. During an initial, bone marrow independent phase of thymus regeneration, cortisone had a stronger inhibitory effect on the cellular regeneration of the organ than irradiation. On the other hand, during a subsequent bone marrow dependent phase, thymus regeneration was impaired by radiation exposure but not by cortisone treatment. In another experimental series, irradiated mice were transplanted with bone marrow cells in different numbers from syngeneic donors which had either been treated with cortisone or were left untreated. Twenty days later the cell number was consistently larger in the thymus of animals which has been transplanted with cortisone treated bone marrow than in the animals transplanted with untreated bone marrow. It is concluded that the thymus lymphocyte precursors in the bone marrow and the early precursors of thymocytes in the thymus differ with regard to their sensitivity to cortisone and radiation and, therefore, may represent two distinct cell types.     

Overexpression of Aurora-A potentiates HRAS-mediated oncogenic transformation and is implicated in oral carcinogenesis

Aurora kinases are known to play a key role in maintaining mitotic fidelity, and overexpression of aurora kinases has been noted in various tumors. Overexpression of aurora kinase activity is thought to promote cancer development through a loss of centrosome or chromosome number integrity. Here we observed augmentation of G12V-mutated HRAS-induced neoplastic transformation in BALB/c 3T3 A31-1-1 cells transfected with Aurora-A. Aurora-A-short hairpin RNA (shRNA) experiments showed that the expression level of Aurora-A determines susceptibility to transformation. Aurora-A gene amplification was noted in human patients with tongue or gingival squamous carcinoma (4/11). Amplification was observed even in pathologically normal epithelial tissue taken at sites distant from the tumors in two patients with tongue cancer. However, overexpression of Aurora-A mRNA was observed only within the tumors of all patients examined (11/11). Our data indicate that Aurora-A gene amplification and overexpression play a role in human carcinogenesis, largely due to the effect of Aurora-A on oncogenic cell growth, rather than a loss of maintenance of centrosomal or chromosomal integrity.