Detection of amplified DNA sequences by reverse chromosome painting using genomic tumor DNA as probe

A modification of reverse chromosome painting was carried out using genomic DNA from tumor cells as a complex probe for chromosomal in situ suppression hybridization to normal metaphase chromsome spreads. Amplified DNA sequences contained in such probes showed specific signals, revealing the normal chromosome positions from which these sequences were derived. As a model system, genomic DNAs were analyzed from three tumor cell lines with amplification units including the proto-oncogene c-myc. The smallest amplification unit was about 90 kb and was present in 16–24 copies; the largest unit was bigger than 600 kb and was present in 16–32 copies. Specific signals that co-localized with a differently labeled c-myc probe on chromosome band 8q24 were obtained with genomic DNA from each cell line. In further experiments, genomic DNA derived from primary tumor material was used in the case of a male patient with glioblastoma multiforme (GBM). Southern blot analysis using an epidermal growth factor receptor gene (EGFR) probe that maps to 7p13 indicated the amplification of sequences from this gene. Using reverse chromosome painting, signals were found both on band 7p13 and bands 12q13–q15. Notably, the signal on 12q13–q15 was consistently stronger. The weaker 7p13 signal showed co-localization with the major signal of the differently labeled EGFR probe. A minor signal of this probe was seen on 12q13, suggesting cross-hybridization to ERB3 sequences homologous to EGFR. The results indicate co-amplification of sequences from bands 12q13–q15, in addition to sequences from band 7p13. Several oncogenes map to 12q13–q15 providing candidate genes for a tumor-associated proto-oncogene amplification. Although the nature of the amplified sequences needs to be clarified, this experiment demonstrates the potential of reverse chromosome painting with genomic tumor DNA for rapidly mapping the normal chromosomal localization of the DNA from which the amplified sequences were derived. In addition, a weaker staining of chromosomes 10 and X was consistently observed indicating that these chromosomes were present in only one copy in the GBM genome. This rapid approach can be used to analyze cases where no metaphase spreads from the tumor material are available. It does not require any preknowledge of amplified sequences and can be applied to screen large numbers of tumors

Architektur für ein System zur Dokumentanalyse im Unternehmenskontext - Integration von Datenbeständen, Aufbau- und Ablauforganisation

Workflowmanagementsysteme werden im Bürobereich verstärkt zur effizienten Geschäftsprozeßabwicklung eingesetzt. Das bereits Mitte der 70er Jahre propagierte papierlose Büro bleibt jedoch gegenwärtig immer noch Utopie. Dieser Widerspruch liegt darin begründet, daß die Handhabung von papierintensiven Vorgängen in hohem Maße abhängig ist von einer Identifkation und Aufbereitung der in den Dokumenten enthaltenen Informationen. Allerdings müssen solche Daten z.B. bei eingehender Post immer noch von Hand eingegeben werden. In diesem Dokument wird die Architektur eines System vorgestellt, das diesen Medienbruch überwinden soll. Techniken aus dem Gebiet der Dokumentanalyse und des Dokumentverstehens werden in den Workftowkontext integriert und nutzen das dort verfügbare Wissen zur Steigerung der Erkennungsqualität. Das Architekturdokument beruht auf einer ebenfalls dokumentierten Anforderungsanalyse (DFKI Dokument D-97-05). Es enthält eine statische und eine dynamische Beschreibung der benötigten Klassenkategorien und erklärt deren Funktionalität anhand eines umfassenden Beispiels

Anforderungen an ein System zur Dokumentanalyse im Unternehmenskontext : Integration von Datenbeständen, Aufbau- und Ablauforganisation

Workflowmanagementsysteme werden im Bürobereich verstärkt zur effizienten Geschäftsprozeßabwicklung eingesetzt. Das bereits Mitte der 70er Jahre propagierte papierlose Büro bleibt jedoch gegenwärtig immer noch Utopie, da auch durch den allgegenwärtigen Einsatz von Computern im Bürobereich der Durchsatz an Schriftstücken nicht gesenkt wird. Insbesondere die Handhabung von papierintensiven Vorgängen ist in hohem Maße abhängig von einer Identifikation und Aufbereitung der in den Dokumenten enthaltenen Informationen. Allerdings müssen solche Daten z. B. bei eingehender Post immer noch von Hand eingegeben werden. In diesem Dokument werden Anforderungen an ein System aufgestellt, das diesen Medienbruch überwinden solI. Techniken aus dem Gebiet der Dokumentanalyse und des Dokumentverstehens werden in den Workflowkontext integriert und nutzen das dort verfügbare Wissen zur Steigerung der Erkennungsqualität. Durch Einschränkung des aktuellen Kontextes - etwa in Form offener Vorgänge - soll eine Erhöhung der Erkennungspräzision erreicht werden. Bei der Beschreibung der Systemanforderungen wurde nach den Richtlinien des V-Modells vorgegangen

The HNF4A R76W mutation causes atypical dominant Fanconi syndrome in addition to a β cell phenotype

types: JOURNAL ARTICLEMutation specific effects in monogenic disorders are rare. We describe atypical Fanconi syndrome caused by a specific heterozygous mutation in HNF4A. Heterozygous HNF4A mutations cause a beta cell phenotype of neonatal hyperinsulinism with macrosomia and young onset diabetes. Autosomal dominant idiopathic Fanconi syndrome (a renal proximal tubulopathy) is described but no genetic cause has been defined.This article presents independent research supported by the National Institute for Health Research (NIHR) Exeter Clinical Research Facility. The research is funded by a Wellcome Trust Senior Investigator Award, (grant number 098395/Z/12/Z).Wellcome Trus

A −436C>A Polymorphism in the Human FAS Gene Promoter Associated with Severe Childhood Malaria

Human genetics and immune responses are considered to critically influence the outcome of malaria infections including life-threatening syndromes caused by Plasmodium falciparum. An important role in immune regulation is assigned to the apoptosis-signaling cell surface receptor CD95 (Fas, APO-1), encoded by the gene FAS. Here, a candidate-gene association study including variant discovery at the FAS gene locus was carried out in a case-control group comprising 1,195 pediatric cases of severe falciparum malaria and 769 unaffected controls from a region highly endemic for malaria in Ghana, West Africa. We found the A allele of c.−436C>A (rs9658676) located in the promoter region of FAS to be significantly associated with protection from severe childhood malaria (odds ratio 0.71, 95% confidence interval 0.58–0.88, pempirical = 0.02) and confirmed this finding in a replication group of 1,412 additional severe malaria cases and 2,659 community controls from the same geographic area. The combined analysis resulted in an odds ratio of 0.71 (95% confidence interval 0.62–0.80, p = 1.8×10−7, n = 6035). The association applied to c.−436AA homozygotes (odds ratio 0.47, 95% confidence interval 0.36–0.60) and to a lesser extent to c.−436AC heterozygotes (odds ratio 0.73, 95% confidence interval 0.63–0.84), and also to all phenotypic subgroups studied, including severe malaria anemia, cerebral malaria, and other malaria complications. Quantitative FACS analyses assessing CD95 surface expression of peripheral blood mononuclear cells of naïve donors showed a significantly higher proportion of CD69+CD95+ cells among persons homozygous for the protective A allele compared to AC heterozygotes and CC homozygotes, indicating a functional role of the associated CD95 variant, possibly in supporting lymphocyte apoptosis

Genomic and transcriptomic changes complement each other in the pathogenesis of sporadic Burkitt lymphoma

Burkitt lymphoma (BL) is the most common B-cell lymphoma in children. Within the International Cancer Genome Consortium (ICGC), we performed whole genome and transcriptome sequencing of 39 sporadic BL. Here, we unravel interaction of structural, mutational, and transcriptional changes, which contribute to MYC oncogene dysregulation together with the pathognomonic IG-MYC translocation. Moreover, by mapping IGH translocation breakpoints, we provide evidence that the precursor of at least a subset of BL is a B-cell poised to express IGHA. We describe the landscape of mutations, structural variants, and mutational processes, and identified a series of driver genes in the pathogenesis of BL, which can be targeted by various mechanisms, including IG-non MYC translocations, germline and somatic mutations, fusion transcripts, and alternative splicing

The genomic and transcriptional landscape of primary central nervous system lymphoma

Primary lymphomas of the central nervous system (PCNSL) are mainly diffuse large B-cell lymphomas (DLBCLs) confined to the central nervous system (CNS). Molecular drivers of PCNSL have not been fully elucidated. Here, we profile and compare the whole-genome and transcriptome landscape of 51 CNS lymphomas (CNSL) to 39 follicular lymphoma and 36 DLBCL cases outside the CNS. We find recurrent mutations in JAK-STAT, NFkB, and B-cell receptor signaling pathways, including hallmark mutations in MYD88 L265P (67%) and CD79B (63%), and CDKN2A deletions (83%). PCNSLs exhibit significantly more focal deletions of HLA-D (6p21) locus as a potential mechanism of immune evasion. Mutational signatures correlating with DNA replication and mitosis are significantly enriched in PCNSL. TERT gene expression is significantly higher in PCNSL compared to activated B-cell (ABC)-DLBCL. Transcriptome analysis clearly distinguishes PCNSL and systemic DLBCL into distinct molecular subtypes. Epstein-Barr virus (EBV)+ CNSL cases lack recurrent mutational hotspots apart from IG and HLA-DRB loci. We show that PCNSL can be clearly distinguished from DLBCL, having distinct expression profiles, IG expression and translocation patterns, as well as specific combinations of genetic alterations

Corporate Interests: How the News Media Portray the Economy

This study examines contradictory claims about the news media's coverage of the economy. After discussing various sociological perspectives on news media, I compare the objective performance of California's economy, as measured by statistical indicators, to accounts of the economy found in the state's largest newspaper—the Los Angeles Times. The data reveal that, despite growth patterns that overwhelmingly favored economic elites, the negative news about the economy disproportionately depicted events and problems affecting corporations and investors instead of the general workforce. When the Times did discuss problems affecting workers, the articles were relatively short, most often placed in the back sections of the newspaper, and rarely discussed policy alternatives to the status quo. Moreover, unlike the viewpoints of business leaders and government officials, the viewpoints of workers or their spokespersons were rarely used as sources of information. These findings provide qualified support for existing scholarship purporting that the news media, when reporting on the economy, privilege the interests of corporations and investors over the interests of the general workforce

Publisher Correction: LifeTime and improving European healthcare through cell-based interceptive medicine.

A Correction to this paper has been published: https://doi.org/10.1038/s41586-021-03287-8.</jats:p

A Framework for Managing Enterprise Architecture Debts - Outline and Research Directions

Even though enterprise architecture management (EAM) offers a wide range of methods and tools for aligning business with IT, an architect’s work is challenged by reality. The evolution of enterprise architecture (EA) and given constraints (e.g. legacy systems and processes) lead to debts which may complicate and hinder opportunities; however, the management of such debts has not been considered in EAM research. This paper presents a framework for strategically managing EA-debt-related issues and propose open questions as well as future research directions in this field