The aryl hydrocarbon receptor (AHR) plays a role in three areas of biology that include the adaptive metabolism of xenobiotics, the toxic responses associated with exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), and vascular remodeling of the developing embryo. To test the hypothesis that receptor signaling in different cell types is responsible for these aspects of AHR biology, we generated a conditional Ahr allele where exon 2 is flanked by loxP sites. Through the use of Cre-lox technology, we then investigated the role of AHR signaling in hepatocytes or endothelial cells in mediating prototypical endpoints of adaptive, toxic, or developmental signaling. Using this model, we provide evidence that AHR signaling in endothelial͞hematopoietic cells is necessary for developmental closure of the ductus venosus, whereas AHR signaling in hepatocytes is necessary to generate adaptive and toxic responses of the liver in response to dioxin exposure. Taken together, these data illustrate the importance of cell-specific receptor signaling for the generation of distinct AHR-dependent physiological outcomes.Cre recombinase ͉ ductus venosus ͉ endothelial cell ͉ hepatocyte ͉ dioxin T he aryl hydrocarbon receptor (AHR) is a basic helix-loophelix͞Per-Arnt-Sim protein that plays an essential role in three areas of biology. In response to polycyclic aromatic hydrocarbons, the AHR up-regulates a battery of xenobiotic metabolizing enzymes that include the cytochromes P450, CYP1A1, CYP1A2, and CYP1B1 as well as the phase II enzymes GST-A1 and UGT1-06 (1, 2). In response to halogenateddibenzo-p-dioxins, AHR activation results in the induction of xenobiotic metabolism plus a variety of toxic responses that include hepatocellular damage, thymic involution, epithelial hyperplasia, teratogenesis, and cancer (3-6). Finally, in response to an unknown developmental cue, the AHR influences normal vascular development, most notably the closure of a fetal vascular structure known as the ductus venosus (DV) (3, 7-9).The mouse liver is a powerful model for investigations related to AHR biology. The mouse system allows the production of recombinant loci by gene targeting, whereas the liver provides a representation of each of the three aspects of AHR signal transduction. Using this model, we have provided evidence to suggest that the intracellular details of AHR signal transduction are similar for the adaptive, toxic, and developmental pathways. Through the use of recombinant Ahr and Arnt alleles, we have shown that AHR activation, AHR translocation to the nucleus, AHR dimerization with the aryl hydrocarbon receptor nuclear translocator (ARNT), and AHR-ARNT binding to dioxin responsive elements within the genome are required for adaptive metabolism, dioxin toxicity, and closure of the DV within the developing liver (3,4,7,8,10).The question of how the AHR is able to produce multiple biological events from a similar signal transduction mechanism remains unclear. We hypothesize that receptor signaling in distinct cell types is responsible ...

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BACKGROUND: Stereotactic body radiotherapy (SBRT) is an alternative to surgery for clinical stage I non-small cell lung cancer (NSCLC), but comparing its effectiveness is difficult because of differences in patient selection and staging. METHODS: Two databases were combined which contained patients treated from 1999 to 2008 by lobectomy (LR, n 5 132), sublobar resection (SLR, n 5 48), and SBRT (n 5 137) after negative staging. Univariate and multivariate analysis were performed for survival (OS), total recurrence control (TRC comprises local-regional and distant control), and locoregional control (LRC) in our entire population. A matchedpair analysis was also performed that compared surgery and SBRT results. Median follow-up for the entire study population was 25.8 months. RESULTS: On univariate analysis, OS was significantly worse with SBRT and also correlated with histology, the Charlson comorbidity index, tumor size, and aspirin use; TRC correlated only with histology; and no variable significantly correlated with LRC. OS was significantly poorer for SBRT in the matched-pair analysis than for patients treated with surgery, but TRC and LRC were not significantly different between these groups. Multivariate analyses including propensity score as a covariate (controlling for all factors affecting treatment selection) found that OS correlated only with Charlson comorbidity index, and TRC correlated only with tumor grade. LRC correlated only with tumor size with or without propensity score correction. CONCLUSIONS: This retrospective study has demonstrated similar OS, LRC, and TRC with SBRT or surgery after controlling for prognostic and patient selection factors. Randomized clinical trials are needed to better compare the effectiveness of these treatments. Cancer 2013;119:2683-91.

Purpose To report the final cosmetic results from a single-arm prospective clinical trial evaluating accelerated partial breast irradiation (APBI) using intensity-modulated radiotherapy (IMRT) with active-breathing control (ABC). Methods/Materials Women greater than 40 years old with stages 0–1 breast cancer who received breast-conserving surgery were enrolled in an institutional review board-approved prospective study evaluating APBI using IMRT administered with deep-inspiration breath-hold. Patients received 38.5 Gy in 3.85 Gy fractions given twice daily over 5 consecutive days. The PTV was defined as the lumpectomy cavity with a 1.5 cm margin. Cosmesis was scored on a 4 category scale by the treating physician. Toxicity was scored according to the National Cancer Institute Common Terminology Criteria For Adverse Events (CTCAE v. 3.0). We report the cosmetic and toxicity results with a median follow-up of 5 years. Results A total of 34 patients were enrolled. Two patients were excluded because of fair baseline cosmesis. The trial was terminated early because fair/poor cosmesis developed in 7 of 32 women with a median follow-up of 2.5 years. At a median follow-up of 5 years, further decline in the cosmetic outcome was observed in 5 women. Cosmesis at time of last assessment was 43.3% excellent, 30% good, 20% fair, and 6.7% poor. Fibrosis according to the CTCAE at last assessment is as follows: 3.3% grade 2 toxicity and 0% grade 3 toxicity. There was no correlation of CTCAE grade 2 or greater fibrosis with cosmesis. The 5-year rate of local control was 97% for all 34 patients initially enrolled. Conclusions In this prospective trial with 5 year median follow-up, we observed an excellent rate of tumor control using IMRT-planned APBI. Cosmetic outcomes, however, continued to decline, with 26.7% of women having a fair to poor cosmetic result. These results underscore the need for continued cosmetic assessment for patients treated with APBI by technique.

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The small but statistically significant benefit in preservation of cardiac LVEF observed here should motivate future studies that include LVEF as a potentially meaningful endpoint. Future studies should disaggregate the impact of IMRT from that of DIBH. Clinical practice should recognize the importance of minimizing cardiac dose, even when already low in comparison to historical levels.

The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) serves as a prototype for a range of environmental toxicants and as a pharmacologic probe to study signal transduction by the aryl hydrocarbon receptor (AHR). Despite a detailed understanding of how TCDD exposure leads to the transcriptional up-regulation of cytochrome P450-dependent monooxygenases, we know little about how compounds like TCDD lead to a variety of AHR-dependent toxic endpoints such as liver pathology, terata, thymic involution and cancer. Using an acute exposure protocol and the toxic response of the mouse liver as a model system, we have begun a detailed microarray analysis to describe the transcriptional changes that occur after various TCDD doses and treatment times. Through correlation analysis of time-and dose-dependent toxicological endpoints, we are able to identify coordinately-responsive transcriptional events that can be defined as primary transcriptional events and downstream events that may represent mechanistically linked sequelae or that have potential as biomarkers of toxicity.