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  • A limitation of this study

    2020-07-08

    A limitation of this study is the between-study heterogeneity of the datasets analyzed. To address this heterogeneity, we used a random-effects model in our analysis. Also, only 2 of the databases provided information on sex, and as a result, the sex-specific analyses were performed with a smaller cohort of samples and therefore have lower statistical power. In addition, it is possible that aneurysm rupture status contributes to the gene expression. However, given the small sample size, subgroup analysis was not performed. Despite these limitations, we identified 3 HATU receptor pathway–associated genes which may be sex-dependent and one, PIK3R1, that is downregulated in both sexes.
    Conclusions We identified 4 estrogen-related genes (PIK3R1, ADCY9, ADCY7, and HBEGF) to be significantly associated with the development of cerebral aneurysms. When sex is taken into account, we found that PIK3R1 was downregulated in both men and women, whereas JUN, ADCY5, and MMP9 were downregulated in women only. Further investigation into the estrogen receptor pathway may provide us with more insight into the mechanism of cerebral aneurysm development and the protective role of estrogens.
    Introduction The objective of this review is to summarize studies that have been done to develop and evaluate fluorescently labeled steroidal estrogens since 1995, the date of the last major review [1]. This review will cover the synthetic approaches used to prepare those agents and to consider their potential as molecular imaging agents to detect and characterize estrogen receptors in the cellular setting. Finally, recommendations will be provided concerning newer approaches for the development of “next-generation” fluorescently labeled estrogens. The rationale for developing fluorescent and other imaging agents for the estrogen receptor lies in its close association with hormone responsive diseases, particularly breast cancer [2]. According to the American Cancer Society, over 266,000 cases of breast cancer were predicted for 2018, and over 40,000 women dying from the disease [3]. It is the most common cancer among women, accounting for 29% of all diagnosed cancers. Because approximately two thirds of breast cancers are dependent on estrogen and/or progesterone, agents that target the estrogen receptor (ER) play a major role in breast cancer therapy. Such strategies include the use of selective estrogen receptor modulators (SERMs), such as tamoxifen, and selective estrogen receptor down-regulators (SERDs), such as fulvestrant [4], [5], [6]. Aromatase inhibitors that suppress estrogen biosynthesis also play a significant role in therapy [7]. Diagnosis and treatment success are assessed by tumor estrogen receptor status, which employs immunohistochemistry (IHC) among other modalities. Although IHC is suitable for assaying the ER expression in biopsy tissues obtained from primary breast tumors, its accuracy becomes lower in metastases [8]. Use of radiolabeled ER-directed tracers offers potential for non-invasive, clinical imaging of both primary and metastatic tumors, however, reviews of that area of research indicate the need for additional improvements before that goal is achieved [2], [9], [10], [11]. At the cellular and molecular level, high spatial resolution is possible using fluorescence imaging methods, if high ER affinity and selectivity were incorporated. The last major review on this topic, with material through 1995 [1], provided the theoretical and practical bases for this area of research. At that time, an imaging agent that met all of the criteria had not been prepared and evaluated. This review focuses on fluorescently labeled steroidal estrogens prepared since 1995, particularly the synthetic approaches, their evaluation as potential molecular imaging agents, and a brief discussion of their advantages/disadvantages. Finally, we will describe our current approach to develop the “next-generation’ fluorescent steroidal ER imaging agent.