Genome-Wide Analysis of Menin Binding Provides Insights into MEN1 Tumorigenesis

Multiple endocrine neoplasia type I (MEN1) is a familial cancer syndrome characterized primarily by tumors of multiple endocrine glands. The gene for MEN1 encodes a ubiquitously expressed tumor suppressor protein called menin. Menin was recently shown to interact with several components of a trithorax family histone methyltransferase complex including ASH2, Rbbp5, WDR5, and the leukemia proto-oncoprotein MLL. To elucidate menin's role as a tumor suppressor and gain insights into the endocrine-specific tumor phenotype in MEN1, we mapped the genomic binding sites of menin, MLL1, and Rbbp5, to approximately 20,000 promoters in HeLa S3, HepG2, and pancreatic islet cells using the strategy of chromatin-immunoprecipitation coupled with microarray analysis. We found that menin, MLL1, and Rbbp5 localize to the promoters of thousands of human genes but do not always bind together. These data suggest that menin functions as a general regulator of transcription. We also found that factor occupancy generally correlates with high gene expression but that the loss of menin does not result in significant changes in most transcript levels. One exception is the developmentally programmed transcription factor, HLXB9, which is overexpressed in islets in the absence of menin. Our findings expand the realm of menin-targeted genes several hundred-fold beyond that previously described and provide potential insights to the endocrine tumor bias observed in MEN1 patients

Risk stratification in primary total joint arthroplasty: the current state of knowledge

Background: As we transition to value-based care delivery models, risk stratification in total joint arthroplasty is more important than ever. The purpose of this study was to identify patients who would likely require higher level of care and may not be suitable for inclusion in bundled payment models. Methods: The American College of Surgeons National Surgical Quality Improvement Program database was queried for all patients who underwent primary total joint arthroplasty between 2011 and 2012. Five types of adverse events were assessed: medical complications, surgical complications, readmission, reoperation, and mortality. Univariate and multivariate logistic regression analyses were performed using a large number of demographic and morbidity variables. Results: A total of 14,185 patients were identified. The 30-day medical complication, surgical complication, readmission, reoperation, and mortality rates were 2.0%, 3.2%, 4.0%, 1.5%, and 0.2%, respectively. Among the different variables assessed, only the American Society of Anesthesiologists (ASA) physical classification system was a significant risk factor for most outcomes assessed. Peripheral vascular disease was the most significant risk factor for medical complications and reoperation (odds ratio, 2.73 and 3.23, respectively). Bleeding disorders were the most significant risk factor for readmission and mortality (odds ratio, 2.03 and 5.86, respectively). Conclusions: ASA score is a more reliable risk stratification tool than Charlson Comorbidity Index, but it is not sufficient by itself. Patients with higher ASA scores combined with peripheral vascular disease and/or bleeding disorders are at especially high risk of developing postsurgical adverse events and may not be suitable for inclusion in bundled payment models. These data can be used to develop better risk stratification models that are critically needed. Keywords: Arthroplasty, Hip, Knee, Risk stratification, ASA physical classification system, Charlson Comorbidity Inde

Factor Occupancy Correlates with High Gene Expression but Absence of Menin Does Not Generally Affect Gene Expression Levels

<div><p>(A) Overall expression of genes for which we had both expression and binding data in HeLa S3 cells was plotted (lane 1, “All expression”) and compared to the expression of genes whose promoter regions were bound (<i>p</i> < 0.0001) by each of the factors indicated at the top. Asterisks denote significance (<i>p</i> < 0.0001) as determined by two-tailed <i>t</i>-test analyses between each set of factor-bound genes compared to all genes. Box plots comparing ChIP-chip and expression data from HepG2 and pancreatic islets revealed similar correlations between expression and factor occupancy (unpublished data).</p><p>(B) Overall expression of genes in islets isolated from wild-type control mice (lane 1, “All Expression”) compared to those normally bound by menin in wild-type islets (lane 2) and those normally bound by menin in islets from 15-wk (lane 3) and 25-wk (lane 4) mice that are conditionally null for <i>Men1</i> (genotype: <i>RIP-cre; Men1</i>^{−<i>/</i>−}).</p></div