Several MR methods have been proposed over the last decade to obtain quantitative estimates of the tissue blood oxygen saturation (StO2) using a quantification of the blood oxygen level dependent effect. These approaches are all based on mathematical models describing the time evolution of the MR signal in biological tissues in the presence of magnetic field inhomogeneities. Although the experimental results are very encouraging, possible biases induced by the model assumptions have not been extensively studied. In this study, a numerical approach was used to examine the influence on T2*, blood volume fraction, and StO2 estimates of possible confounding factors such as water diffusion, intravascular signal, and presence of arterial blood in the voxel. To evaluate the impact of the vessel geometry, straight cylinders and realistic data from two‐photon microscopy for microvascular geometry were compared. Our results indicate that the models are sufficiently realistic, based on a good correlation between ground truth and MR estimates of StO2. Magn Reson Med, 2012. © 2011 Wiley Periodicals, Inc.

Uterine fibroids (leiomyomas or myomas), benign monoclonal tumors, are the most common benign tumors in women. Heavy or prolonged menstrual bleeding, abnormal uterine bleeding, resultant anemia, pelvic pain, infertility, and/or recurrent pregnancy loss are generally associated with uterine fibroids. Although curative treatment of this tumor relies on surgical therapies, medical treatments are considered the first-line treatment to preserve fertility and avoid or delay surgery. The aim of this review is to provide available and emerging medical treatment options for symptomatic uterine fibroids. Literature review and consensus of expert opinion. Many uterine fibroids are asymptomatic and require no intervention, although it is advisable to follow-up patients to document stability in size and growth. Fibroid-associated symptoms include heavy menstrual bleeding and pain or pelvic discomfort. The association between infertility and fibroids increases with age. Treatment options for symptomatic uterine fibroids — include medical, surgical, and radiologically guided interventions. Various medical therapies are now available for women with uterine fibroids, although each therapy has its own advantages and disadvantages. Currently, gonadotrophin-releasing hormone (GnRH) agonists and selective progesterone receptor modulators (SPRMs) are the most effective medical therapies, with the most evidence to support their reduction of fibroid volume and symptomatic improvement in menstrual bleeding. The choice of treatment depends on the patient's personal treatment goals, as well as efficacy and need for repeated interventions.

In the present study, we have investigated the effects of BRCA1 on xenobiotic stress-inducible gene expression. In response to aryl hydrocarbon receptor (AhR) ligands, cytoplasmic AhR becomes activated and then translocates to the nucleus where it forms a complex with the aryl hydrocarbon receptor nuclear translocator (ARNT). Subsequently, the AhR⅐ARNT complex binds to the enhancer or promoter of genes containing a xenobiotic stress-responsive element and regulates the expression of multiple target genes including cytochrome P450 subfamily polypeptide 1 (CYP1A1). In this study, we have found that endogenous and overexpressed exogenous wild-type BRCA1 affect xenobiotic stress-induced CYP1A1 gene expression. Using a standard chromatin immunoprecipitation assay, we have demonstrated that BRCA1 is recruited to the promoter regions of CYP1A1 and CYP1B1 along with ARNT and/or AhR following xenobiotic exposure. Our findings suggest that BRCA1 may be physiologically important for mounting a normal response to xenobiotic insults and that it may function as a coactivator for ARNT activity. Using immunoprecipitation, Western blotting, and glutathione S-transferase capture assays, a xenobiotic-independent interaction between BRCA1 and ARNT has been identified, although it is not yet known whether this is a direct or indirect interaction. We have also found that the inducibility of CYP1A1 and CYP1B1 transcripts following xenobiotic stress was significantly attenuated in BRCA1 knockdown cells. This reduced inducibility is associated with an altered stability of ARNT and was almost completely reversed in cells transfected with an ARNT expression vector. Finally, we have found that xenobiotic (TCDD) treatments of breast cancer cells containing reduced levels of BRCA1 cause the transcription factor ARNT to become unstable.Inherited mutations in the breast cancer susceptibility gene BRCA1 confer increased risk of breast and ovarian cancer (1, 2). In addition, because BRCA1 expression is often decreased or even absent in sporadic breast and ovarian cancer, abnormal BRCA1 expression may also have a role(s) in nonhereditary tumors (3, 4). Although these observations indicate that BRCA1 may act as a tumor suppressor in breast cancer, the specific function(s) of BRCA1 that could have this effect is still not completely understood. However, numerous studies have shown that BRCA1 regulates various pivotal cellular processes, such as cell cycle progression, DNA repair, apoptosis, and transcription, and many of the mechanisms involved have been identified (see Ref. 5 for a review). Recent studies show that BRCA1 proteins are also required for maintaining chromosome stability by regulating centrosome duplication and mitotic spindle checkpoints (6 -8).Although BRCA1 regulates transcription, the mechanisms involved are unlike classical transcriptional factors that directly bind DNA sequences. Rather, BRCA1 regulates transcription via protein-protein interactions. The BRCA1 C-terminal activation domain is responsible for transactivation in ye...

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A recent study of breast cancer patients with and without BRCA1 gene mutations found significantly lower levels of VEGF in serum from patients with BRCA1 mutations (Tarnowski, B., Chudecka-Glaz, A., Gorski, B., and Rzepka-Gorska, I. (2004) Breast Cancer Res. Treat. 88, 287-288). Here, we describe a possible mechanistic explanation for this correlation. Because hypoxia in tumors stimulates VEGF expression and secretion we hypothesized that altered BRCA1 protein levels in breast tumors could affect hypoxia-stimulated VEGF promoter activity. This possibility was tested in cells transfected with various combinations of expression plasmids for BRCA1, BRCA1 specific inhibitory RNAs (BRCA1-siRNAs), HIF-1␣, and a VEGF promoter-reporter and then incubated in normoxia (21%, O 2 ) or hypoxia (0.1%, O 2 ). As predicted, increased BRCA1 levels enhanced both hypoxia-stimulated VEGF promoter activity and the amounts of VEGF mRNA, as determined by semiquantitative RT-PCR and quantitative real time PCR. Using the ChIP assay, we discovered that BRCA1 could be recruited to the endogenous human VEGF promoter along with HIF-1␣ following hypoxia. An interaction between BRCA1 and HIF-1␣ was found in human breast cancer cells. We also found that hypoxia-stimulated VEGF promoter activity and secretion was reduced in cells containing reduced amounts of endogenous BRCA1 protein (obtained by transfecting with BRCA1 siRNAs). A mechanistic explanation for these effects is provided by our finding a reduced half-life and reduced accumulation of HIF-1␣ in hypoxic cells transfected with BRCA1-siRNAs and that proteasome inhibitors blocked these effects of BRCA1-siRNAs. Thus, our results suggest that normal amounts of BRCA1 function in hypoxia to regulate HIF-1␣ stability, probably by interacting with HIF-1␣.