Increased Expression of PcG Protein YY1 Negatively Regulates B Cell Development while Allowing Accumulation of Myeloid Cells and LT-HSC Cells

Ying Yang 1 (YY1) is a multifunctional Polycomb Group (PcG) transcription factor that binds to multiple enhancer binding sites in the immunoglobulin (Ig) loci and plays vital roles in early B cell development. PcG proteins have important functions in hematopoietic stem cell renewal and YY1 is the only mammalian PcG protein with DNA binding specificity. Conditional knock-out of YY1 in the mouse B cell lineage results in arrest at the pro-B cell stage, and dosage effects have been observed at various YY1 expression levels. To investigate the impact of elevated YY1 expression on hematopoetic development, we utilized a mouse in vivo bone marrow reconstitution system. We found that mouse bone marrow cells expressing elevated levels of YY1 exhibited a selective disadvantage as they progressed from hematopoietic stem/progenitor cells to pro-B, pre-B, immature B and re-circulating B cell stages, but no disadvantage of YY1 over-expression was observed in myeloid lineage cells. Furthermore, mouse bone marrow cells expressing elevated levels of YY1 displayed enrichment for cells with surface markers characteristic of long-term hematopoietic stem cells (HSC). YY1 expression induced apoptosis in mouse B cell lines in vitro, and resulted in down-regulated expression of anti-apoptotic genes Bcl-xl and NFκB2, while no impact was observed in a mouse myeloid line. B cell apoptosis and LT-HSC enrichment induced by YY1 suggest that novel strategies to induce YY1 expression could have beneficial effects in the treatment of B lineage malignancies while preserving normal HSCs

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Machine Based Rejection of Low-Quality Spectra, and estimation of brain tumor probabilities from magnetic resonance spectroscopic images

Magnetic resonance spectroscopic images (MRSI) carry spatially resolved information about the in vivo metabolism, however, their evaluation is di#cult. Problems arise especially from artifacts and noise, yielding non-evaluable signals in many voxels. We propose a two-step approach to the processing of MRSI. In the first step a non-linear classifier is employed in every voxel to determine whether the spectral signal is evaluable, and if so, the tumor probability is computed in the second step. Thus, the quality control is strictly separated from the diagnostic evaluation of the spectrum. For an assessment of the proposed approach we consider MRSI-based brain tumor detection and localization and a tumor probability mapping by pattern recognition. In a quantitative comparison against the standard operator-controlled processing our interaction-free approach shows similar to superior performance

Optimal Classification of Long Echo Time In Vico Magnetic Resonance Spectra in the Detection of Recurrent Brain Tumor

We present an optimal high-level postprocessing of single-voxel H magnetic resonance spectra, and assess the benefits and limitations of automated methods as diagnostic aids in the detection of recurrent brain tumor

Dynamic Contrast-Enhanced Magnetic Resonance Imaging Rapidly Indicates Vessel Regression in Human Squamous Cell Carcinomas Grown in Nude Mice Caused by VEGF Receptor 2 Blockade with DC101

The purpose of our study was the investigation of early changes in tumor vascularization during antiangiogenic therapy with the vascular endothelial growth factor (VEGF) receptor 2 antibody (DC101) using dynamic contrast-enhanced magnetic resonance imaging (DCE MRI). Subcutaneous heterotransplants of human skin squamous cell carcinomas in nude mice were treated with DC101. Animals were examined before and repeatedly during 2 weeks of antiangiogenic treatment using Gd-DTPA-enhanced dynamic T1-weighted MRI. With a two-compartment model, dynamic data were parameterized in “amplitude” (increase of signal intensity relative to precontrast value) and k(ep) (exchange rate constant). Data obtained by MRI were validated by parallel examinations of histological sections immunostained for blood vessels (CD31). Already 2 days after the first DC101 application, a decrease of tumor vascularization was observed, which preceded a reduction of tumor volume. The difference between treated tumors and controls became prominent after 4 days, when amplitudes of treated tumors were decreased by 61% (P = .02). In line with change of microvessel density, the decrease in amplitudes was most pronounced in tumor centers. On day 7, the mean tumor volumes of treated (153 ± 843 mm(3)) and control animals (596 ± 384 mm(3)) were significantly different (P = .03). After 14 days, treated tumors showed further growth reduction (83 ± 93 mm(3)), whereas untreated tumors (1208 ± 822 mm(3)) continued to increase (P = .02). Our data underline the efficacy of DC101 as antiangiogenic treatment in human squamous cell carcinoma xenografts in nude mice and indicate DCE MRI as a valuable tool for early detection of treatment effects before changes in tumor volume become apparent

Potential Applications of Flat-Panel Volumetric CT in Morphologic and Functional Small Animal Imaging

Noninvasive radiologic imaging has recently gained considerable interest in basic and preclinical research for monitoring disease progression and therapeutic efficacy. In this report, we introduce flat-panel volumetric computed tomography (fpVCT) as a powerful new tool for noninvasive imaging of different organ systems in preclinical research. The three-dimensional visualization that is achieved by isotropic high-resolution datasets is illustrated for the skeleton, chest, abdominal organs, and brain of mice. The high image quality of chest scans enables the visualization of small lung nodules in an orthotopic lung cancer model and the reliable imaging of therapy side effects such as lung fibrosis. Using contrast-enhanced scans, fpVCT displayed the vascular trees of the brain, liver, and kidney down to the subsegmental level. Functional application of fpVCT in dynamic contrast-enhanced scans of the rat brain delivered physiologically reliable data of perfusion and tissue blood volume. Beyond scanning of small animal models as demonstrated here, fpVCT provides the ability to image animals up to the size of primates