Apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE/Ref -1)

■ Abstract Cells in multicellular organisms are exposed to both endogenous oxidative stresses generated metabolically and to oxidative stresses that originate from neighboring cells and from other tissues. To protect themselves from oxidative stress, cells are equipped with reducing buffer systems (glutathione/GSH and thioredoxin/thioredoxin reductase) and have developed several enzymatic mechanisms against oxidants that include catalase, superoxide dismutase, and glutathione peroxidase. Other major extrinsic defenses (from the diet) include ascorbic acid, β-carotene and other carotenoids, and selenium. Recent evidence indicates that in addition to their antioxidant function, several of these redox species and systems are involved in regulation of biological processes, including cellular signaling, transcription factor activity, and apoptosis in normal and cancer cells. The survival and overall well-being of the cell is dependent upon the balance between the activity and the intracellular levels of these antioxidants as well as their interaction with various regulatory factors, including Ref-1, nuclear factor-κB, and activating protein-1.

Key Points Question How has opioid use in pediatric patients changed over the past 10 years, and what factors are associated with differences in opioid use? Findings A cross-sectional study of 69 152 emergency department visits found that opioid prescribing rates decreased between 2006 to 2010 (8.23%) and 2011 to 2015 (6.30%). Region, race, age, and payment method were associated with differences in opioid prescribing. Meaning Opioid rates have decreased in recent years but inconsistencies in prescribing continue, suggesting the need for further research.

A non-sinusoidal trajectory profile is proposed for the oscillating hydrofoil in the energy generators instead of conventional sinusoidal plunging/pitching motions to seek better energy extraction performance. The novel profile is achieved by combining a specially designed trapezoidal-like pitching motion with a sinusoidal plunging motion and investigated numerically on its output energy coefficient and total output efficiency. Through an adjustable parameter b, the pitching profile can be altered from a sinusoidal (b ¼ 1.0) to a square wave (b / N). In this work, a series of b ranging from 1.0 to 4.0 are investigated to examine the effect of combined motion trajectory on the energy extraction performance. The study encompasses the Strouhal numbers (St) from 0.05 to 0.5, nominal effective angle of attacks a0 of 10 and 20 and plunging amplitude h0/c of 0.5 and 1.0. Numerical results show that, for different b pitching motions, a larger a0 always results in a higher extraction power Cop and total efficiency hT. Compared with the sinusoidal motion (b ¼ 1), significant increment of Cop and hT can be observed for b > 1 over a certain range of St. The investigation also shows that there exists an optimal pitching profile which may increase the output power coefficient and total output efficiency as high as 63% and 50%, respectively, over a wide range of St. Detailed examination on the computed results reveal that, the energy extraction performance is determined by the relative ratio of the positive and negative contributions from the different combination of lift force, momentum and corresponding plunging velocity and pitching angular velocity, all of which are considerably affected by b

Nuclear factor kappa B (NFκB) is an essential regulator of gene transcription for hundreds of genes, including many critically involved in apoptosis. NFκB complexes containing cRel generally activate pro‐apoptotic genes, while those with RelA activate anti‐apoptotic genes. We have previously shown that NFκB binding by RelA is constitutively elevated in human metastatic melanoma cultures relative to normal melanocytes. Here we extended our investigation to immunohistochemical analysis of human tissue biopsies. We found that RelA expression is significantly elevated in melanocytes of human naevi and melanomas relative to normal skin, but expression of its inhibitor IκB‐α is significantly lower in metastatic melanomas than in intradermal naevi. Antibodies specific for the nuclear localization signal of RelA also showed significantly increased staining in metastatic melanoma biopsies. Notably, in melanomas and in naevi, we also found that RelA is phosphorylated at serine 529, and this activated form accumulates in the nuclei of melanomas. This suggests that increased expression and phosphorylation of RelA occurs at the stage of the benign naevus, but IκB‐α is able to sequester RelA in the cytoplasm and regulate RelA transcriptional transactivation. We also found that antibodies against cRel show a progressive increase in staining from naevi to melanoma. However, staining for IκB‐ɛ, which primarily inhibits the nuclear localization of cRel was also progressively increased, and cRel expression was predominantly cytoplasmic in melanomas. These results confirm that the altered expression of RelA found in metastatic melanoma cells in tissue culture is relevant to human tumors and offer new insights into the deregulation of NFκB signaling.