DNA microarray data integration by ortholog gene analysis reveals potential molecular mechanisms of estrogen-dependent growth of human uterine fibroids

BACKGROUND: Uterine fibroids or leiomyoma are a common benign smooth muscle tumor. The tumor growth is well known to be estrogen-dependent. However, the molecular mechanisms of its estrogen-dependency is not well understood. METHODS: Differentially expressed genes in human uterine fibroids were either retrieved from published papers or from our own statistical analysis of downloaded array data. Probes for the same genes on different Affymetrix chips were mapped based on probe comparison information provided by Affymetrix. Genes identified by two or three array studies were submitted for ortholog analysis. Human and rat ortholog genes were identified by using ortholog gene databases, HomoloGene and TOGA and were confirmed by synteny analysis with MultiContigView tool in the Ensembl genome browser. RESULTS: By integrated analysis of three recently published DNA microarray studies with human tissue, thirty-eight genes were found to be differentially expressed in the same direction in fibroid compared to adjacent uterine myometrium by at least two research groups. Among these genes, twelve with rat orthologs were identified as estrogen-regulated from our array study investigating uterine expression in ovariectomized rats treated with estrogen. Functional and pathway analyses of the twelve genes suggested multiple molecular mechanisms for estrogen-dependent cell survival and tumor growth. Firstly, estrogen increased expression of the anti-apoptotic PCP4 gene and suppressed the expression of growth inhibitory receptors PTGER3 and TGFBR2. Secondly, estrogen may antagonize PPARγ signaling, thought to inhibit fibroid growth and survival, at two points in the PPAR pathway: 1) through increased ANXA1 gene expression which can inhibit phospholipase A2 activity and in turn decrease arachidonic acid synthesis, and 2) by decreasing L-PGDS expression which would reduce synthesis of PGJ2, an endogenous ligand for PPARγ. Lastly, estrogen affects retinoic acid (RA) synthesis and mobilization by regulating expression of CRABP2 and ALDH1A1. RA has been shown to play a significant role in the development of uterine fibroids in an animal model. CONCLUSION: Integrated analysis of multiple array datasets revealed twelve human and rat ortholog genes that were differentially expressed in human uterine fibroids and transcriptionally responsive to estrogen in the rat uterus. Functional and pathway analysis of these genes suggest multiple potential molecular mechanisms for the poorly understood estrogen-dependent growth of uterine fibroids. Fully understanding the exact molecular interactions among these gene products requires further study to validate their roles in uterine fibroids. This work provides new avenues of study which could influence the future direction of therapeutic intervention for the disease

Are Democracies Truly Bad at Intelligence? An Analysis of Counterintelligence vs. Intelligence and State Structure

Frequently, intelligence scholars and historians make the charge that democracies are inherently worse at intelligence work than authoritarian states. However, this claim has never been tested. This study seeks to advance the discussion of intelligence and counterintelligence effectiveness through an analysis of how the level of democratization within a state relates to its intelligence structure – a critical variable when assessing the effectiveness of an intelligence apparatus. Avoiding judgment on the morality of intelligence actions and refraining from a discussion of effectiveness, my aim is to answer this question – what is the relationship between democratization and intelligence structure? Utilizing a comparative case study method and building on the theoretical foundations of intelligence scholars like Thomas Bruneau, Roy Godson, and Hank Prunckun, this study analyzes the primary intelligence structures and relevant history of Pakistan, Russia, India, Israel, the United States, and the United Kingdom. The overall intelligence organizations of these states are then classified according to their operational control, structure, and emphasis, paying special attention to the distinction between counterintelligence and intelligence

An Unlikely Hero: How Virginia Hall Became the Most Feared Allied Spy in Occupied France, and Why You\u27ve Never Heard of Her

In the history of espionage, World War II intelligence contributions typically take a backseat to those of the Cold War despite the fact that the American Office of Strategic Services and British Special Operations Executive provided critical support to the Allied victory. An even less-studied aspect of intelligence history is the involvement of women, particularly during World War II. This project focuses upon the contributions of a singular woman who served in both the Office of Strategic Services and the Special Operations Executive, but has remained largely unrecognized in historiography despite her unmatched achievements. Examining primary source material and authoritative treatments of relevant intelligence history, this study recounts and contextualizes the achievements of Virginia Hall while analyzing bias in the historiography of World War II and mid-twentieth century American intelligence. Virginia Hall was a remarkable intelligence practitioner during and after World War II, despite the obstacles she faced as a disabled woman. Her story deserves to be told