SOD1, SOD2, and catalase had lower expression in PIN and prostate carcinoma than in benign epithelium. The number of immunoreactive cells in PIN was similar to cancer, indicating that these are closely related. Enzyme activities were variable, with no difference between benign epithelial cells and cancer, although this lack of change in enzyme activity could have been due to the presence of contaminating benign cells within the cancer specimens. The results of reactive oxygen species damage were found only in the epithelium and not in the stroma. Expression of the DNA adduct 8-hydroxydeoxyguanosine was present in fewer than 3% of cells, with no apparent differences among benign epithelium, PIN, and cancer. These findings suggest that oxidative stress is an early event in carcinogenesis.
The Ten Eleven Translocation (TET) enzymes have been found to be mutated in both diffuse large B-cell (DLBCL) and peripheral T-cell (PTCL) lymphomas resulting in DNA hypermethylation. Recent studies in embryonal stem cells showed that ascorbic acid (AA) is a cofactor for TET with a binding site at the catalytic domain, and enhances TET activity. We hypothesized that AA could potentially enhance TET activity in lymphoma cells to cause DNA demethylation, reactivate expression of tumor suppressor genes and enhance chemosensitivity. We demonstrate in vitro that AA treatment of DLBCL and PTCL cells using AA concentrations achievable intravenously increased TET activity leading to DNA demethylation. This epigenetic effect is independent of hydrogen peroxide. AA treatment increased the expression of SMAD1, a tumor suppressor gene known to be suppressed by methylation, and increased chemosensitivity of lymphoma cells. Twenty-nine percent (10/34) of unselected lymphoma patients had plasma AA levels that were deficient suggesting an additional clinical mechanism of TET hypofunction. These data indicate that AA has the potential to modify TET function in lymphoma and enhance chemosensitivity. In addition, the AA deficiency seen in some patients may further impair TET function and contribute to resistance. Clinical trials testing intravenous AA with chemotherapy are warranted.
Social insect sex and caste ratios are well-studied targets of evolutionary conflicts, but the heritable factors affecting these traits remain unknown. To elucidate these factors, we carried out a short-term artificial selection study on female caste ratio in the ant Monomorium pharaonis. Across three generations of bidirectional selection, we observed no response for caste ratio, but sex ratios rapidly became more female-biased in the two replicate high selection lines and less female-biased in the two replicate low selection lines. We hypothesized that this rapid divergence for sex ratio was caused by changes in the frequency of infection by the heritable bacterial endosymbiont Wolbachia, because the initial breeding stock varied for Wolbachia infection, and Wolbachia is known to cause female-biased sex ratios in other insects. Consistent with this hypothesis, the proportions of Wolbachia-infected colonies in the selection lines changed rapidly, mirroring the sex ratio changes. Moreover, the estimated effect of Wolbachia on sex ratio (~13% female bias) was similar in colonies before and during artificial selection, indicating that this Wolbachia effect is likely independent of the effects of artificial selection on other heritable factors. Our study provides evidence for the first case of endosymbiont sex ratio manipulation in a social insect.
Abstract-Tissue factor (TF) is a low-molecular-weight glycoprotein that initiates the extrinsic clotting cascade and is considered a major regulator of arterial thrombogenicity. TF pathway inhibitor (TFPI) is a major physiological inhibitor of TF-initiated coagulation. The aim of this study was to define the complex interplay between TF and TFPI and the regulation of vascular thrombogenicity in a model of vascular remodeling. To determine the levels and pattern of vascular expression of TF and TFPI associated with vascular remodeling, a murine model of flow cessation was studied. A rterial thrombosis is the proximate cause of myocardial infarction and stroke. Biochemical and clinical evidence suggests the importance of the thrombogenic nature of atherosclerotic vessels in this process. Tissue factor (TF), a low-molecular-weight glycoprotein that initiates the extrinsic clotting cascade, is considered a major regulator of coagulation, hemostasis, and thrombogenicity of atherosclerotic arteries. 1-9 TF pathway inhibitor (TFPI), which provides physiological inhibition of TF-initiated coagulation by binding to factor Xa and the TF-factor VIIa complex in a 2-step process, is found in vascular endothelium and smooth muscle cells as well as in platelets, blood monocytes, and macrophages. 10 -14 In atherosclerotic carotid arteries, TF expression is abundant, whereas TFPI expression is limited in up to 30% of plaques, resulting in predominant TF activity. 15 In plaque, where TFPI expression is the greatest, TF activity is attenuated. Thus, this imbalance between TF and TFPI expression in plaque may result in the prothrombotic phenotype associated with atherosclerosis. To investigate the development and potential regulation of this imbalance, a well-defined murine model of vascular remodeling, including neointimal formation, was studied. 16 Materials and Methods Animal ModelThe murine model of vascular remodeling associated with carotid flow cessation as described by Kumar and Lindner 16 was used. All procedures complied with the standards for care and use of animal subjects as stated in the Guide for the Care and Use of Laboratory Animals (Institute of Laboratory Animal Resources, National Academy of Sciences, Bethesda, Md). Briefly, via a ventral longitudinal incision, the left common carotid of adult C57BL/6 mice was identified and ligated with 4-0 silk just proximal to the bifurcation. The midline incision was closed with 6-0 vicryl, and the skin was closed with a Nexaband topical skin closure kit supplied by Veterinary Products Laboratories. Warmed lactated Ringer's solution (1 mL SC) and Enrofloxacin (Bayer) (0.01 mL IM) were injected, and the mice were allowed to recover on a warm hydrothermal pad. At 1, 2, 3, and 4 weeks, the ligated carotid arteries were harvested as fresh frozen specimens for protein analysis, or they were harvested after perfusion fixation at physiological pressure with 10% formalin before euthanasia. Tissue Processing and AnalysisThe carotid arteries were obtained from mice, thoroughly rinse...
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