Cholesterol-loaded macrophage foam cells are a central component of atherosclerotic lesions. ABCA1, the defective molecule in Tangier disease, mediates the efflux of phospholipids and cholesterol from cells to apoA-I, reversing foam cell formation. In ABCA1, we identified a sequence rich in proline, glutamic acid, serine, and threonine (PEST sequence) that enhances the degradation of ABCA1 by calpain protease and thereby controls the cell surface concentration and cholesterol efflux activity of ABCA1. In an apparent positive feedback loop, apoA-I binds ABCA1, promotes lipid efflux, inhibits calpain degradation, and leads to increased levels of ABCA1. ApoA-I infusion also increases ABCA1 in vivo. These studies reveal a novel mode of regulation of ABCA1 by PEST sequence–mediated calpain proteolysis that appears to be reversed by apolipoprotein-mediated phospholipid efflux. Inhibition of ABCA1 degradation by calpain could represent a novel therapeutic approach to increasing macrophage cholesterol efflux and decreasing atherosclerosis

ATP-binding cassette transporter 1 (ABCA1), the defective transporter in Tangier disease, binds and promotes cellular cholesterol and phospholipid efflux to apolipoprotein I (apoA-I). Based on a high degree of sequence homology between ABCA1 and ABCA7, a transporter of unknown function, we investigated the possibility that ABCA7 might be involved in apolipoprotein binding and lipid efflux. Similarly to cells expressing ABCA1, HEK293 cells overexpressing ABCA7 showed specific binding and cross-linking of lipid-poor apoA-I. ABCA7 expression increased cellular phosphatidylcholine and sphingomyelin efflux to apoA-I in a manner similar to ABCA1 but had no effect on cholesterol efflux. Western analysis showed a high protein level of ABCA7 in mouse spleen, lung, adrenal, and brain but low expression in liver. In contrast to ABCA1, ABCA7 showed moderate basal mRNA and protein levels in macrophages and lymphocytes but no induction by liver X receptor activation. These studies show that ABCA7 has the ability to bind apolipoproteins and promote efflux of cellular phospholipids without cholesterol, and they suggest a possible role of ABCA7 in cellular phospholipid metabolism in peripheral tissues.

Purpose To extract and study comprehensive spatial–temporal 18F-FDG PET features for the prediction of pathologic tumor response to neoadjuvant chemoradiotherapy (CRT) in esophageal cancer. Methods and Materials Twenty patients with esophageal cancer were treated with trimodality therapy (CRT plus surgery) and underwent FDG PET/CT scans both before (pre-CRT) and after (post-CRT) CRT. The two scans were rigidly registered. A tumor volume was semiautomatically delineated using a threshold of standardized uptake value (SUV) ≥ 2.5, followed by manual editing. Comprehensive features were extracted to characterize the SUV intensity distribution, spatial patterns (texture), tumor geometry, and associated changes resulting from CRT. The usefulness of each feature in predicting pathologic tumor response to CRT was evaluated using the area under the receiver operating characteristic curve (AUC). Results The best traditional response measure was maximum SUV (SUVmax) decline (AUC 0.76). Two new intensity features (SUVmean decline and skewness) and three texture features (inertia, correlation, and cluster prominence) were found to be significant predictors with AUCs ≥ 0.76. According to these features, a tumor was more likely a responder when the mean SUV decline was larger, when there were relatively fewer voxels with higher SUVs pre-CRT, or when FDG uptake post-CRT was relatively homogeneous. All of the most accurate predictive features were extracted from the entire tumor rather than from the most active part of the tumor. For SUV intensity features and tumor size features, changes were more predictive than pre- or post-CRT assessments alone. Conclusion Spatial–temporal FDG PET features were found to be useful predictors of pathologic tumor response to neoadjuvant chemoradiotherapy in esophageal cancer. Key words: FDG PET/CT, Tumor response, Esophageal cancer, Quantitative image analysis

BACKGROUND.This study was designed to investigate the fluorine‐18 fluorodeoxyglucose (FDG)‐positron emission tomography (PET) imaging characteristics of triple‐negative (estrogen receptor‐negative [ER−]/progesterone receptor‐negative [PR−]/HER2‐negative [HER2−]) breast carcinoma and compare the results with characteristics of ER+/PR+/HER2− breast carcinomas, which usually carry a favorable prognosis.METHODS.Patients with newly diagnosed breast carcinoma who had undergone dual‐time‐point FDG‐PET before any therapeutic intervention and were identified as either ER−/PR−/HER2− or ER+/PR+/HER2− (the control group) on histopathology of the surgical specimen, were considered candidates for inclusion in this analysis. These patients underwent FDG‐PET as a component of a prospective study that evaluated the role of multimodality imaging for characterizing primary breast lesions and locoregional staging. Breast cancer lesions were imaged twice at approximately 63 minutes and 101 minutes after the administration of FDG. Maximum standardized uptake values (SUVmax) were measured at both time points (SUVmax1 and SUVmax2) to analyze the data generated. After FDG‐PET imaging, the patients underwent either breast‐conserving surgery or mastectomy, and histopathology reports were used to provide the definitive diagnosis against which the PET study results were compared.RESULTS.In total, 88 patients with breast cancer (29 patients with ‘triple‐negative’ breast cancer and 59 patients with ER+/PR+/HER2− breast malignancies) were selected among 206 individuals who were enrolled in the study protocol. The ‘triple‐negative’ group comprised 14.08% of the total study population. The age of the patients with this subtype of tumor ranged from 33 years to 75 years (mean age±standard deviation, 51.6 ± 10.1 years), and tumors in this subgroup ranged in size from 0.9 cm to 6 cm (mean size, 1.99 cm). Among the histopathologic subtypes, 25 tumors were infiltrating ductal carcinoma (86%), and 1 tumor each (3.5% each subtype) was lobular, mixed ductal‐lobular, medullary, and tubular. For the calculation of FDG‐PET parameters in this group, only patients who had undergone FDG‐PET studies before any intervention were considered, and 18 patients in the triple‐negative group met this criterion. According to same criterion, a control group of 59 patients with ER+/PR+/HER2− cancer who had focal FDG uptake were selected for comparison with the triple‐negative population. The breast cancer lesions were observed as areas with focally enhanced uptake of FDG in all patients (sensitivity, 100%) in the triple‐negative group. The mean (±standard deviation) SUVmax1 of the primary lesion for the triple‐negative group was 7.27 ± 5.6, the mean SUVmax2 was 8.29 ± 6.4, and the percentage change in SUVmax (%ΔSUVmax) was 14.3 ± 15.8%. In the control group of 59 patients with ER+/PR+/HER2− breast carcinoma, the mean values for SUVmax1, SUVmax2, and %ΔSUVmax were 2.68 ± 1.9, 2.84 ± 2.2, and 3.7 ± 13.0%, respectively. The mean values for SUVmax1, SUVmax2, and %Dgr;SUVmax in the triple‐negative group were significantly higher compared with the values in the nontriple‐negative control group (P = .0032, P = .002, and P = .017, respectively). When the 2 subgroups were compared according to tumor size, grade, and stage, the SUVmax1 was significantly higher in the triple‐negative group for both size categories (5.4 vs 1.9, P = .006; and 9.2 vs 3.5, P = .04) and for grade 3 tumors (9.1 vs 3.9, P = .022). The %ΔSUVmax values for patients in the triple‐negative group who had tumors that measured ≤2 cm and > 2 cm were 14.8 and 13.8, respectively; and the corresponding values for patients in the control group were 0.6 and 6.7, respectively. Although the mean %ΔSUVmax clearly was higher in the triple‐negative group for both tumor size categories, comparison between the 2 groups demonstrated a statistically significant difference in tumors that measured ≤2 cm (P = .016). The authors also observed that, in the triple‐negative group, tumor grades were correlated significantly with the magnitude of SUVmax1 and SUVmax2 (P = .012 and P = .01, respectively). Stage for stage, tumors from the triple‐negative group appeared to have a higher mean SUVmax1 compared with tumors from nontriple‐negative control group. However, the trend reached statistical significance in patients with stage II disease.CONCLUSIONS.Triple‐negative breast tumors were associated with enhanced FDG uptake commensurate with their aggressive biology and were detected with very high sensitivity by using FDG‐PET imaging. Cancer 2008. © 2007 American Cancer Society.

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