Das Levitenhaus : häusliche Ceremonial- u. Ritual-Gesetze, das Schema-Lesen, Schaufäden, Denkriemen, Hebe am Teige, Lichtanzünden, u. das Fleischsalzen enthaltend ; a. d. Hebr. bearb. u. mit Erklärungen versehen

Isaac Landau

Resistance prediction in AML: analysis of 4601 patients from MRC/NCRI, HOVON/SAKK, SWOG and MD Anderson Cancer Center

Therapeutic resistance remains the principal problem in acute myeloid leukemia (AML). We used area under receiver-operating characteristic curves (AUCs) to quantify our ability to predict therapeutic resistance in individual patients, where AUC=1.0 denotes perfect prediction and AUC=0.5 denotes a coin flip, using data from 4601 patients with newly diagnosed AML given induction therapy with 3+7 or more intense standard regimens in UK Medical Research Council/National Cancer Research Institute, Dutch–Belgian Cooperative Trial Group for Hematology/Oncology/Swiss Group for Clinical Cancer Research, US cooperative group SWOG and MD Anderson Cancer Center studies. Age, performance status, white blood cell count, secondary disease, cytogenetic risk and FLT3-ITD/NPM1 mutation status were each independently associated with failure to achieve complete remission despite no early death (‘primary refractoriness’). However, the AUC of a bootstrap-corrected multivariable model predicting this outcome was only 0.78, indicating only fair predictive ability. Removal of FLT3-ITD and NPM1 information only slightly decreased the AUC (0.76). Prediction of resistance, defined as primary refractoriness or short relapse-free survival, was even more difficult. Our limited ability to forecast resistance based on routinely available pretreatment covariates provides a rationale for continued randomization between standard and new therapies and supports further examination of genetic and posttreatment data to optimize resistance prediction in AML.

Linking the SUMO protease SENP5 to neutrophil differentiation of AML cells

In an mRNA profiling screen performed to unveil novel mechanisms of leukemogenesis, we found that the sentrin-specific protease 5 (SENP5) was significantly repressed in clinical acute myeloid leukemia when compared to healthy neutrophil samples. SENP5 is an enzyme that targets and cleaves small ubiquitin-like modifier (SUMO) residues from SUMOylated proteins. Further investigation with AML neutrophil differentiation cell models showed increased SENP5 expression upon induction of differentiation; in contrast, knocking down SENP5 resulted in significantly attenuated neutrophil differentiation. Our results support a new role of SENP5 in AML pathology, and in particular in the neutrophil differentiation of myeloid leukemic cells.

Disease evolution and outcomes in familial AML with germline CEBPA mutations

In-depth molecular investigation of familial leukemia has been limited by the rarity of recognized cases. This study examines the genetic events initiating leukemia and details the clinical progression of disease across multiple families harboring germ-line CEBPA mutations. Clinical data were collected from 10 CEBPA-mutated families, representing 24 members with acute myeloid leukemia (AML). Whole-exome (WES) and deep sequencing were performed to genetically profile tumors and define patterns of clonal evolution. Germline CEBPA mutations clustered within the N-terminal and were highly penetrant, with AML presenting at a median age of 24.5 years (range, 1.75-46 years). In all diagnostic tumors tested (n = 18), double CEBPA mutations (CEBPAdm) were detected, with acquired (somatic) mutations preferentially targeting the C-terminal. Somatic CEBPA mutations were unstable throughout the disease course, with different mutations identified at recurrence. Deep sequencing of diagnostic and relapse paired samples confirmed that relapse-associated CEBPA mutations were absent at diagnosis, suggesting recurrence was triggered by novel, independent clones. Integrated WES and deep sequencing subsequently revealed an entirely new complement of mutations at relapse, verifying the presentation of a de novo leukemic episode. The cumulative incidence of relapse in familial AML was 56% at 10 years (n = 11), and 3 patients experienced ≥3 disease episodes over a period of 17 to 20 years. Durable responses to secondary therapies were observed, with prolonged median survival after relapse (8 years) and long-term overall survival (10-year overall survival, 67%). Our data reveal that familial CEBPA-mutated AML exhibits a unique model of disease progression, associated with favorable long-term outcomes.

The RNA binding proteins RBM38 and DND1 are repressed in AML and have a novel function in APL differentiation

The RNA binding proteins RBM binding motif protein 38 (RBM38) and DEAD END 1 (DND1) selectively stabilize mRNAs by attenuating RNAse activity or protecting them from micro(mi)RNA-mediated cleavage. Furthermore, both proteins can efficiently stabilize the mRNA of the cell cycle inhibitor p21(CIP1). Since acute myeloid leukemia (AML) differentiation requires cell cycle arrest and RBM38 as well as DND1 have antiproliferative functions, we hypothesized that decreased RBM38 and DND1 expression may contribute to the differentiation block seen in this disease. We first quantified RBM38 and DND1 mRNA expression in clinical AML patient samples and CD34(+) progenitor cells and mature granulocytes from healthy donors. We found significantly lower RBM38 and DND1 mRNA levels in AML blasts and CD34(+) progenitor cells as compared to mature neutrophils from healthy donors. Furthermore, the lowest expression of both RBM38 and DND1 mRNA correlated with t(8;21). In addition, neutrophil differentiation of CD34(+) cells in vitro with G-CSF (granulocyte colony stimulating factor) resulted in a significant increase of RBM38 and DND1 mRNA levels. Similarly, neutrophil differentiation of NB4 acute promyelocytic leukemia (APL) cells was associated with a significant induction of RBM38 and DND1 expression. To address the function of RBM38 and DND1 in neutrophil differentiation, we generated two independent NB4RBM38 as well as DND1 knockdown cell lines. Inhibition of both RBM38 and DND1 mRNA significantly attenuated NB4 differentiation and resulted in decreased p21(CIP1) mRNA expression. Our results clearly indicate that expression of the RNA binding proteins RBM38 and DND1 is repressed in primary AML patients, that neutrophil differentiation is dependent on increased expression of both proteins, and that these proteins have a critical role in regulating p21(CIP1) expression during APL differentiation.

A General Schema for Optimal Monetary Policymaking: Objectives and Rules

This paper examines four equivalent methods of optimal monetary policymaking, committing to the social loss function, using discretion with the central bank long-run and short-run loss functions, and following monetary policy rules. All lead to optimal economic performance. The same performance emerges from these different policymaking methods because the central bank actually follows the same (similar) policy rules. These objectives (the social loss function, the central bank long-run and short-run loss functions) and monetary policy rules imply a complete regime for optimal policy making. The central bank long-run and short-run loss functions that produce the optimal policy with discretion differ from the social loss function. Moreover, the optimal policy rule emerges from the optimization of these different central bank loss functions.

Graetzens Schema zu einer enzyklopädischen Bearbeitung des Talmud

Philipp Bloch

Cassiodori ... doctissima et religiosissima Psalterij dauidici expositio : q[uam] plurima enucleans que vel idioma aliquod diuino eloquio propriu[m] vel dogma singulare vel diffinitione[m], vel schema, vel etymologia[m], vel interpretatione[m], vel rhetor

Sign.: a10, b-z8, [et]8, [cum]8, [rum]8, A-C8, D-E6

Generación automática de la configuración de subestaciones eléctricas según el Estándar IEC 61850 a partir de una herramienta de diseño gráfico

La evolución de las redes eléctricas se dirige hacia lo que se conoce como “Smart Grids” o “Redes Eléctricas Inteligentes”. Estas “Smart Grids” se componen de subestaciones eléctricas, que a su vez se componen de unos dispositivos llamados IEDs (Dispositivos Electrónicos Inteligentes – Intelligent Electronic Devices). El diseño de IEDs se encuentra definido en la norma IEC 61850, que especifica además un Lenguaje de Configuración de Subestaciones (Substation Configuration Language SCL) para la definición de la configuración de subestaciones y sus IEDs. Hoy en día, este estándar internacional no sólo se utiliza para diseñar correctamente IEDs y asegurar su interoperabilidad, sino que también se utiliza para el diseño de otros dispositivos de la red eléctrica, como por ejemplo, medidores inteligentes. Sin embargo, aunque existe una tendencia cada vez mayor del uso de este estándar, la comprensión y el manejo del mismo resulta difícil debido al gran volumen de información que lo compone y del nivel de detalle que utiliza, por lo que su uso para el diseño de IEDs se hace tedioso sin la ayuda de un soporte software. Es por ello que, para facilitar la aplicación del estándar IEC 61850 en el diseño de IEDs se han desarrollado herramientas como “Visual SCL”, “SCL Explorer” o “61850 SCLVisual Design Tool”. En concreto, “61850 SCLVisual Design Tool” es una herramienta gráfica para el modelado de subestaciones electricas, generada mediante el uso de los frameworks Eclipse Modeling Framework (EMF) y Epsilon Generative Modeling Technologies (GMT) y desarrollada por el grupo de investigación SYST de la UPM. El objetivo de este proyecto es añadir una nueva funcionalidad a la herramienta “61850 Visual SCL DesignTool”. Esta nueva funcionalidad consiste en la generación automática de un fichero de configuración de subestaciones eléctricas según el estándar IEC 61850 a partir de de una herramienta de diseño gráfico. Este fichero, se denomina SCD (Substation Configuration Description), y se trata de un fichero XML conforme a un esquema XSD (XML Schema Definition) mediante el que se define el lenguaje de configuración de subestaciones SCL del IEC 61850. Para el desarrollo de este proyecto, es necesario el estudio del lenguaje para la configuración de subestaciones SCL, así como del lenguaje gráfico específico de dominio definido por la herramienta “61850 SCLVisual Design Tool”, la estructura de los ficheros SCD, y finalmente, del lenguaje EGL (Epsilon Generation Language) para la transformación y generación automática de código a partir de modelos EMF. ABSTRACT Electrical networks are evolving to “Smart Grids”. Smart Grids are composed of electrical substations that in turn are composed of devices called IEDs (Intelligent Electronic Devices). The design of IEDs is defined by the IEC 61850 standard, which also specifies a Substation Configuration Languaje (SCL) used to define the configuration of substations and their IEDs. Nowadays, this international standard is not only used to design properly IEDs and guarantee their interoperability, but it is also used to design different electrical network devices, such as, smart meters. However, although the use of this standard is growing, its compression as well as its management, is still difficult due to its large volume of information and its level of detail. As a result, designing IEDs becomes a tedious task without a software support. As a consequence of this, in order to make easier the application of the IEC 61850 standard while designing IEDs, some software tools have been developed, such as: “Visual SCL”, “SCL Explorer” or “61850 SCLVisual Design Tool”. In particular, “61850 SCLVisual Design Tool” is a graphical tool used to make electrical substations models, and developed with the Eclipse Modeling Framework (EMF) and Epsilon Generative Modeling Technologies (GMT) by the research group SYST of the UPM. The aim of this project is to add a new functionality to “61850 Visual SCL DesignTool”. This new functionality consists of the automatic code generation of a substation configuration file according to the IEC 61850 standard. This file is called SCD (Substation Configuration Description), and it is a XML file that follows a XSD (XML Schema Definition) that defines the Substation Configuration Language (SCL) of the IEC 61850. In order to develop this project, it is necessary to study the Substation Configuration Language (SCL), the domain-specific graphical languaje defined by the tool “61850 SCLVisual Design Tool”, the structure of a SCD file, and the Epsilon Generation Language (EGL) used for the automatic code generation from EMF models

Human AML1/MDS1/EVI1 fusion protein induces an acute myelogenous leukemia (AML) in mice: A model for human AML

The human t(3;21)(q26;q22) translocation is found as a secondary mutation in some cases of chronic myelogenous leukemia during the blast phase and in therapy-related myelodysplasia and acute myelogenous leukemia. One result of this translocation is a fusion between the AML1, MDS1, and EVI1 genes, which encodes a transcription factor of approximately 200 kDa. The role of the AML1/MDS1/EVI1 (AME) fusion gene in leukemogenesis is largely unknown. In this study, we analyzed the effect of the AME fusion gene in vivo by expressing it in mouse bone marrow cells via retroviral transduction. We found that mice transplanted with AME-transduced bone marrow cells suffered from an acute myelogenous leukemia (AML) 5–13 mo after transplantation. The disease could be readily transferred into secondary recipients with a much shorter latency. Morphological analysis of peripheral blood and bone marrow smears demonstrated the presence of myeloid blast cells and differentiated but immature cells of both myelocytic and monocytic lineages. Cytochemical and flow cytometric analysis confirmed that these mice had a disease similar to the human acute myelomonocytic leukemia. This murine model for AME-induced AML will help dissect the molecular mechanism of AML and the molecular biology of the AML1, MDS1, and EVI1 genes.

Subnuclear targeting of Runx/Cbfa/AML factors is essential for tissue-specific differentiation during embryonic development

Runx (Cbfa/AML) transcription factors are critical for tissue-specific gene expression. A unique targeting signal in the C terminus directs Runx factors to discrete foci within the nucleus. Using Runx2/CBFA1/AML3 and its essential role in osteogenesis as a model, we investigated the fundamental importance of fidelity of subnuclear localization for tissue differentiating activity by deleting the intranuclear targeting signal via homologous recombination. Mice homozygous for the deletion (Runx2ΔC) do not form bone due to maturational arrest of osteoblasts. Heterozygotes do not develop clavicles, but are otherwise normal. These phenotypes are indistinguishable from those of the homozygous and heterozygous null mutants, indicating that the intranuclear targeting signal is a critical determinant for function. The expressed truncated Runx2ΔC protein enters the nucleus and retains normal DNA binding activity, but shows complete loss of intranuclear targeting. These results demonstrate that the multifunctional N-terminal region of the Runx2 protein is not sufficient for biological activity. We conclude that subnuclear localization of Runx factors in specific foci together with associated regulatory functions is essential for control of Runx-dependent genes involved in tissue differentiation during embryonic development.

An AML-1 consensus sequence binds an osteoblast-specific complex and transcriptionally activates the osteocalcin gene.

Tissue and cell-type specific expression of the rat osteocalcin (rOC) gene involves the interplay of multiple transcriptional regulatory factors. In this report we demonstrate that AML-1 (acute myeloid leukemia-1), a DNA-binding protein whose genes are disrupted by chromosomal translocations in several human leukemias, interacts with a sequence essential for enhancing tissue-restricted expression of the rOC gene. Deletion analysis of rOC promoter-chloramphenicol acetyltransferase constructs demonstrates that an AML-1-binding sequence within the proximal promoter (-138 to -130 nt) contributes to 75% of the level of osteocalcin gene expression. The activation potential of the AML-1-binding sequence has been established by overexpressing AML-1 in osteoblastic as well as in nonosseous cell lines. Overexpression not only enhances rOC promoter activity in osteoblasts but also mediates OC promoter activity in a nonosseous human fibroblastic cell line. A probe containing this site forms a sequence specific protein-DNA complex with nuclear extracts from osteoblastic cells but not from nonosseous cells. Antisera supershift experiments indicate the presence of AML-1 and its partner protein core-binding factor beta in this osteoblast-restricted complex. Mutations of the critical AML-1-binding nucleotides abrogate formation of the complex and strongly diminish promoter activity. These results indicate that an AML-1 related protein is functional in cells of the osteoblastic lineage and that the AML-1-binding site is a regulatory element important for osteoblast-specific transcriptional activation of the rOC gene.

Das Verzeichniss der Vielperzentigen : ein zeitgemässer Schema renomirter kapitalisten Wiens, die für zwölf, achtzehn, vier und zwanzig, sechs und dreissig und mehr Perzent ihr Geld ausleihen /

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