Genome-Wide Maps of Circulating miRNA Biomarkers for Ulcerative Colitis

Inflammatory Bowel Disease – comprised of Crohn's Disease and Ulcerative Colitis (UC) - is a complex, multi-factorial inflammatory disorder of the gastrointestinal tract. In this study we have explored the utility of naturally occurring circulating miRNAs as potential blood-based biomarkers for non-invasive prediction of UC incidences. Whole genome maps of circulating miRNAs in micro-vesicles, Peripheral Blood Mononuclear Cells and platelets have been constructed from a cohort of 20 UC patients and 20 normal individuals. Through Significance Analysis of Microarrays, a signature of 31 differentially expressed platelet-derived miRNAs has been identified and biomarker performance estimated through a non-probabilistic binary linear classification using Support Vector Machines. Through this approach, classifier measurements reveal a predictive score of 92.8% accuracy, 96.2% specificity and 89.5% sensitivity in distinguishing UC patients from normal individuals. Additionally, the platelet-derived biomarker signature can be validated at 88% accuracy through qPCR assays, and a majority of the miRNAs in this panel can be demonstrated to sub-stratify into 4 highly correlated intensity based clusters. Analysis of predicted targets of these biomarkers reveal an enrichment of pathways associated with cytoskeleton assembly, transport, membrane permeability and regulation of transcription factors engaged in a variety of regulatory cascades that are consistent with a cell-mediated immune response model of intestinal inflammation. Interestingly, comparison of the miRNA biomarker panel and genetic loci implicated in IBD through genome-wide association studies identifies a physical linkage between hsa-miR-941 and a UC susceptibility loci located on Chr 20. Taken together, analysis of these expression maps outlines a promising catalog of novel platelet-derived miRNA biomarkers of clinical utility and provides insight into the potential biological function of these candidates in disease pathogenesis

An overlooked connection: serotonergic mediation of estrogen-related physiology and pathology

BACKGROUND: In humans, serotonin has typically been investigated as a neurotransmitter. However, serotonin also functions as a hormone across animal phyla, including those lacking an organized central nervous system. This hormonal action allows serotonin to have physiological consequences in systems outside the central nervous system. Fluctuations in estrogen levels over the lifespan and during ovarian cycles cause predictable changes in serotonin systems in female mammals. DISCUSSION: We hypothesize that some of the physiological effects attributed to estrogen may be a consequence of estrogen-related changes in serotonin efficacy and receptor distribution. Here, we integrate data from endocrinology, molecular biology, neuroscience, and epidemiology to propose that serotonin may mediate the effects of estrogen. In the central nervous system, estrogen influences pain transmission, headache, dizziness, nausea, and depression, all of which are known to be a consequence of serotonergic signaling. Outside of the central nervous system, estrogen produces changes in bone density, vascular function, and immune cell self-recognition and activation that are consistent with serotonin's effects. For breast cancer risk, our hypothesis predicts heretofore unexplained observations of the opposing effects of obesity pre- and post-menopause and the increase following treatment with hormone replacement therapy using medroxyprogesterone. SUMMARY: Serotonergic mediation of estrogen has important clinical implications and warrants further evaluation

Abstract 4825: Common genetic pathways are involved in canine diffuse large B cell lymphoma relapse and human diffuse large B cell lymphoma lympomagenesis

Abstract Background/Purpose: The genetic complexity of lymphoma is gradually being unraveled; however, new and better approaches to a molecular understanding are needed. Dogs make an exceptional model for the study of lymphoma because lymphoma occurs spontaneously in this species with a relatively high frequency and it shares many morphological and clinical characteristics with human lymphoma. Very little is known about genetic influences on time to relapse in the most common type of lymphoma in both humans and dogs – diffuse large B-cell lymphoma (DLBCL). Thus, the aim of this study was to determine what genes and pathways are significantly correlated with time to relapse in dogs with spontaneously occurring DLBCL treated with combination chemotherapy. Methods: Snap frozen lymph node biopsy samples were taken from dogs diagnosed with DLBCL prior to chemotherapy treatment and upon relapse. A total of 31 paired tissue samples were acquired, and a subset of 20 samples were used for this analysis. Affymetrix Canine 2.0 Genechips were used for expression profiling. Spearman's Rank Correlation (SRC) was used to detect genes correlated with clinically relevant quantitative traits. Of available measures, time to relapse provided the most power and was the most relevant to the human condition. Results: One known pathway altered in human DLBCL involves BCL6. Our analysis found a significant gene expression signature for BCL6 pathways associated with relapsed patients (Fisher's Exact Test, p=0.0005375). Additionally, we reviewed multiple pathways associated with time to relapse and identified a novel unregulated gene- STAP1- that is highly correlated with time to relapse (r = 0.81, p=0.0000018). A protein encoded by this gene functions as a docking protein, acting downstream of Tec tyrosine kinase in B-cell antigen receptor signaling and has not been previously associated with lymphoma. NSMAF, part of the ceramide lipid signaling pathway, was also significantly correlated with patient time to relapse (r=0.76, p=.000014). NSMAF is required for TNF-mediated activation of neutral sphingomyelinase and may play a role in regulating TNF-induced cellular responses such as inflammation, proliferation, and apoptosis. Interestingly, STAP1 has been associated with lipid levels in human subjects. While further validation is required to confirm the results, these findings hint at previously unknown signaling interactions. Conclusion: We identified genes and pathways that were significantly related to patient time to relapse in canine DLBCL. These results suggest that canine DLBCL shares molecular features with human DLBCL, but also exhibits unique interactions of signaling pathways. Taken together, this validates the dog as a model for the study of DLBCL and lends insight into pathways that may lead to the development of novel therapeutic targets. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4825. doi:10.1158/1538-7445.AM2011-4825</jats:p