Inflammatory responses to metal oxide ceramic nanopowders.

Ceramic orthopaedic implants are increasingly popular due to the need for robust total joint replacement implants that have a high success rate long-term and do not induce biological responses in patients. This study was designed to investigate the biological effects of ceramic nanopowders containing aluminium oxide or zirconium oxide to activate the human macrophage THP-1 cell line. In vitro investigation of pro-inflammatory gene expression and chemokine secretion was performed studied using RT-qPCR and ELISA, respectively. TLR4 inhibition, using a small-molecule inhibitor, was used to determine whether ceramic-mediated inflammation occurs in a similar manner to that of metals such as cobalt. THP-1 macrophages were primed with ceramics or LPS and then treated with ATP or ceramics, respectively, to determine whether these nanopowders are involved in the priming or activation of the NLRP3 inflammasome through IL-1ß secretion. Cells treated with ceramics significantly increased pro-inflammatory gene expression and protein secretion which was attenuated through TLR4 blockade. Addition of ATP to cells following ceramic treatment significantly increased IL-1ß secretion. Therefore, we identify the ability of ceramic metal oxides to cause a pro-inflammatory phenotype in THP-1 macrophages and propose the mechanism by which this occurs is primarily via the TLR4 pathway which contributes to inflammasome signalling.

Mapping density response in maize: a direct approach for testing genotype and treatment interactions.

Maize yield improvement has been strongly linked to improvements in stress tolerance, particularly to increased interplant competition. As a result, modern hybrids are able to produce kernels at high plant population densities. Identification of the genetic factors responsible for density response in maize requires direct testing of interactions between genetic effects and density and evaluation of that response in multiple traits. In this article we take a broad view of the problem and use a general approach based upon mixed models to analyze data from eight segmental inbred lines in a B73 background and their crosses to the unrelated parent Mo17 (hybrids). We directly test for the interaction between treatment effects and genetic effects instead of the commonly used overlaying of results on a common map. Additionally, we demonstrate one way to handle heteroscedasticity of variances common in stress responses. We find that some SILs are consistently different from the recurrent parent regardless of the density, while others differ from the recurrent parent in one density level but not in the other. Thus, we find positive evidence for both main effects and interaction between genetic loci and density in cases where the approach of overlapping results fails to find significant results. Furthermore, our study clearly identifies segments that respond differently to density depending upon the inbreeding level (inbred/hybrid).

Natural history of more than 20 years of node-positive primary breast carcinoma treated with cyclophosphamide, methotrexate, and fluorouracil-based adjuvant chemotherapy: a study by the Cancer and Leukemia Group B.

PURPOSE: Breast cancer heterogeneity dictates lengthy follow-up to assess outcomes. Efficacy differences for three regimens that are based on adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) are presented in this article, but cancer recurrence sites, time of relapse, subsequent primary cancers, and causes of death in the natural history of node-positive breast cancer are emphasized. PATIENTS AND METHODS: Beginning in 1975, 905 patients with node-positive cancer were randomly assigned to receive CMF or two regimens of CMF plus other agents. Median follow-up is 22.6 years. The natural-history analysis was performed on a subset of 814 patients. RESULTS: Eighty percent of the 599 women known to have died, died of metastatic breast cancer. Only 8.5% of the deceased women died of a cause other than breast cancer, a second or third cancer, or adjuvant chemotherapy toxicity. One hundred five women (12.8%) developed other primary cancers, with 49 (46.6%) occurring in the contralateral breast. Therapeutic efficacy differences of the CMF regimens reported earlier have been maintained more than 20 years later. For certain subsets, the five-drug regimen had advantages over CMF. Bone was the most common recurrence site. The longest interval to relapse has been 23.5 years, and 18% of those who relapsed did so more than 10 years later. CONCLUSION: Despite adjuvant chemotherapy, a large majority (80%) of women with node-positive breast cancer die of the disease, and many recurrences develop more than 10 years later. CMF plus vincristine and prednisone provides a benefit compared with CMF, but the magnitude varies with the number of involved nodes. Outcome trends in earlier analyses of this study were maintained even years later.

Inhibition of NADPH oxidase activation in endothelial cells by ortho-methoxy-substituted catechols.

NADPH oxidase is a major enzymatic source of oxygen free radicals in stimulated endothelial cells (ECs). The ortho-methoxy-substituted catechol, apocynin (4-hydroxy-3-methoxyacetophenone), isolated from the traditional medicinal plant Picrorhiza kurroa, inhibits the release of superoxide anion (O2*-) by this enzyme. The compound acts by blocking the assembly of a functional NADPH oxidase complex. The underlying chemistry of this inhibitory activity, and its physiological significance to EC proliferation, have been investigated. A critical event is the reaction of ortho-methoxy-substituted catechols with reactive oxygen species (ROS) and peroxidase. Analysis of this reaction reveals that apocynin is converted to a symmetrical dimer through the formation of a 5,5' carbon-carbon bond. Both reduced glutathione and L-cysteine inhibit this dimerization process. Catechols without the ortho-methoxy-substituted group do not undergo this chemical reaction. Superoxide production by an endothelial cell-free system incubated with apocynin was nearly completely inhibited after a lagtime for inhibition of ca. 2 min. Conversely, O2*- production was nearly completely inhibited, without a lagtime, by incubation with the dimeric form of apocynin. The apocynin dimer undergoes a two-electron transfer reaction with standard redox potentials of -0.75 and -1.34 V as determined by cyclic voltammetry. Inhibition of endothelial NADPH oxidase by apocynin caused a dose-dependent inhibition of cell proliferation. These findings identify a metabolite of an ortho-methoxy-substituted catechol, which may be the active compound formed within stimulated ECs that prevents NADPH oxidase complex assembly and activation.