Comparison of DNA methylation, together with mRNA levels, revealed significant differences between AMD versus normal retinas. The evidence presented suggests that GSTM1 and GSTM5 undergo epigenetic repression in AMD RPE/choroid, which may increase susceptibility to oxidative stress in AMD retinas.
Dexras1, a small G-protein localized predominantly to the brain, is transcriptionally upregulated by the synthetic glucocorticoid dexamethasone. It has close homology to the Ras subfamily, but differs in that Dexras1 contains an extended 7 kDa C-terminal tail. Previous studies in our laboratory showed that NMDA receptor activation, via NO and Dexras1, physiologically stimulates DMT1, the major iron importer. A membrane permeable iron chelator substantially reduces NMDA-excitotoxicity suggesting that Dexras1-mediated iron influx plays a crucial role in NMDA/NO-mediated cell death. We here report that iron influx is elicited by nitric oxide but not by other pro-apoptotic stimuli such as H2O2 or staurosporine. Deletion of Dexras1 in mice attenuates NO-mediated cell death in dissociated primary cortical neurons and retinal ganglion cells in vivo. Thus Dexras1 appears to mediate NMDA-elicited neurotoxicity via NO and iron influx.
These data provide proof of principle that the oral iron chelator DFP can protect the retina against diverse insults. Further testing of DFP in additional animal retinal degeneration models at a range of doses is warranted.
The retina can be shielded by the blood-retinal barrier. Because photoreceptors are damaged by excess iron, it is important to understand whether the blood-retinal barrier protects against high serum iron levels. Bone morphogenic protein 6 (Bmp6) knockout mice have serum iron overload. Herein, we tested whether the previously documented retinal iron accumulation in Bmp6 knockout mice might result from the high serum iron levels or, alternatively, low levels of retinal hepcidin, an iron regulatory hormone whose transcription can be up-regulated by Bmp6. Furthermore, to determine whether increases in serum iron can elevate retinal iron levels, we i.v. injected iron into wild-type mice. Retinas were analyzed by real-time quantitative PCR and immunofluorescence to assess the levels of iron-regulated genes/proteins and oxidative stress. Retinal hepcidin mRNA levels in Bmp6 knockout retinas were the same as, or greater than, those in age-matched wild-type retinas, indicating that Bmp6 knockout does not cause retinal hepcidin deficiency. Changes in mRNA levels of L ferritin and transferrin receptor indicated increased retinal iron levels in i.v. iron-injected wild-type mice. Oxidative stress markers were elevated in photoreceptors of mice receiving i.v. iron. These findings suggest that elevated serum iron levels can overwhelm local retinal iron regulatory mechanisms.
These findings indicate that iron absorbed from the diet can modestly increase the level of iron deposition in the wild-type mouse RPE without causing RPE or retinal degeneration. This suggests regulation of retinal iron uptake at the blood-retinal barriers.
Sonography is commonly used as an adjunct to mammography for early detection of breast cancer. We are developing methods to classify solid breast masses in sonograms as malignant or benign. The goal of this study was to combine two independent probabilistic classifiers to improve computer-aided diagnosis of breast masses. Naïve Bayes and logistic regression were used for supervised classification of masses from extracted morphological sonographic features, in combination with mammographic BI-RADS (categories 1 to 5) and patient age.
Solid masses with biopsy-proven diagnoses were analyzed. Training and testing were performed using leave-one-out cross validation. Diagnostic performance was evaluated by the area under the curve (AUC) of the receiver operating characteristic (ROC). Agreement between predictions from the two classifiers was used to differentiate benign and malignant masses. The resultsshow that logistic regression and Naïve Bayes performed with ROC area of 0.902 ± 0.023 and 0.865 ± 0.027, respectively. The combined use of logistic regression and Naïve Bayes demonstrated reduction in biopsies by 48%, with malignancy missed in 2% of cases (false negative rate of 6.4%).Index Terms -quantitative breast ultrasound; computer-aided diagnosis; breast cancer; machine learning.
A naïve Bayes model provides a systematic approach for combining sonographic features and other patient characteristics for assessing the probability of malignancy to differentiate malignant and benign breast masses.
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