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Uncontrolled proliferation and altered metabolic reprogramming are hallmarks of cancer. Active glycolysis and glutaminolysis are characteristic features of these hallmarks and required for tumorigenesis. A fine balance between cancer metabolism and autophagy is a prerequisite of homeostasis within cancer cells. Here we show that glutamate pyruvate transaminase 2 (GPT2), which serves as a pivot between glycolysis and glutaminolysis, is highly upregulated in aggressive breast cancers, particularly the triple negative breast cancer (TNBC) subtype. Abrogation of this enzyme results in decreased TCA cycle intermediates, which promotes the rewiring of glucose carbon atoms and alterations in nutrient levels. Concordantly, loss of GPT2 results in an impairment of mechanistic target of rapamycin complex 1 (mTORC1) activity as well as the induction of autophagy. Furthermore, in vivo xenografts studies have shown that autophagy induction correlates with decreased tumor growth and that markers of induced autophagy correlate with low GPT2 levels in patient samples. Taken together, these findings indicate that cancer cells have a close network between metabolic and nutrient sensing pathways necessary to sustain tumorigenesis, and that aminotransferase reactions play an important role in maintaining this balance.

Uncontrolled proliferation and altered metabolic reprogramming are hallmarks of cancer. Active glycolysis and glutaminolysis are characteristic features of these hallmarks and required for tumorigenesis. A fine balance between cancer metabolism and autophagy is a prerequisite of homeostasis within cancer cells. Here we show that glutamate pyruvate transaminase 2 (GPT2), which serves as a pivot between glycolysis and glutaminolysis, is highly upregulated in aggressive breast cancers, particularly the triple-negative breast cancer subtype. Abrogation of this enzyme results in decreased tricarboxylic acid cycle intermediates, which promotes the rewiring of glucose carbon atoms and alterations in nutrient levels. Concordantly, loss of GPT2 results in an impairment of mechanistic target of rapamycin complex 1 activity as well as the induction of autophagy. Furthermore, in vivo xenograft studies have shown that autophagy induction correlates with decreased tumor growth and that markers of induced autophagy correlate with low GPT2 levels in patient samples. Taken together, these findings indicate that cancer cells have a close network between metabolic and nutrient sensing pathways necessary to sustain tumorigenesis and that aminotransferase reactions play an important role in maintaining this balance. © 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

Hintergrund: Die Ursache des Glaukoms ist bisher unzureichend geklärt. In früheren Studien konnten bereits Hinweise auf eine Rolle des Immunsystems in der Pathogenese gefunden werden. In einem experimentellen autoimmunen Glaukommodell in der Ratte konnten glaukomatöse Schäden reproduziert[zum vollständigen Text gelangen Sie über die oben angegebene URL], 179. Versammlung des Vereins Rheinisch-Westfälischer Augenärzte

International audience; Here we report the new features and improvements in our latest release of the H-Invitational Database (H-InvDB; http://www.h-invitational.jp/), a comprehensive annotation resource for human genes and transcripts. H-InvDB, originally developed as an integrated database of the human transcriptome based on extensive annotation of large sets of full-length cDNA (FLcDNA) clones, now provides annotation for 120 558 human mRNAs extracted from the International Nucleotide Sequence Databases (INSD), in addition to 54 978 human FLcDNAs, in the latest release H-InvDB_4.6. We mapped those human transcripts onto the human genome sequences (NCBI build 36.1) and determined 34 699 human gene clusters, which could define 34 057 (98.1%) protein-coding and 642 (1.9%) non-protein-coding loci; 858 (2.5%) transcribed loci overlapped with predicted pseudogenes. For all these transcripts and genes, we provide comprehensive annotation including gene structures, gene functions, alternative splicing variants, functional non-protein-coding RNAs, functional domains, predicted sub cellular localizations, metabolic pathways, predictions of protein 3D structure, mapping of SNPs and microsatellite repeat motifs, co-localization with orphan diseases, gene expression profiles, orthologous genes, protein-protein interactions (PPI) and annotation for gene families. The current H-InvDB annotation resources consist of two main views: Transcript view and Locus view and eight sub-databases: the DiseaseInfo Viewer, H-ANGEL, the Clustering Viewer, G-integra, the TOPO Viewer, Evola, the PPI view and the Gene family/group.

Inhalt eines Forschungsprojektes der Firma OTEC Präzisionsfinish GmbH und des Fraunhofer-Instituts für Produktionsanlagen und Konstruktionstechnik IPK ist die Entwicklung eines Maschinenprototypen zur Feinbearbeitung mit automatisierter Qualitätskontrolle durch integrierte optische Messtechnik und Messsoftware. Im Rahmen des durch das Zentrale Innovationsprogramm Mittelstand (ZIM) vom Bundesministerium für Wirtschaft und Energie (BMWi) geförderten Projektes wurde dazu eine kompakte, für die Automatisierung und Integration von Messtechnik ausgelegte Maschine entwickelt. Mithilfe dieser Maschine können Werkstücke, wie etwa Nockenwellen oder Zerspanwerkzeuge, mit dem Verfahren Tauchgleitläppen bearbeitet und definierte Kantenradien erzeugt sowie in einem automatisierten Prozess gemessen werden. This paper presents a machine prototype for the finishing of edges and surfaces of work pieces. The prototype has an integrated optical measurement device, which can be used for the control of the process results and possibly automated remachining. The machine is used for the preparation of milling tools. Process parameters and their effects are analyzed and an approach for the automated setting of the process parameters is shown.

Gastrointestinal stromal tumors (GISTs) have distinct gene expression patterns according to localization, genotype and aggressiveness. DNA methylation at CpG dinucleotides is an important mechanism for regulation of gene expression. We performed targeted DNA methylation analysis of 1.505 CpG loci in 807 cancer-related genes in a cohort of 76 GISTs, combined with genome-wide mRNA expression analysis in 22 GISTs, to identify signatures associated with clinicopathological parameters and prognosis. Principal component analysis revealed distinct DNA methylation patterns associated with anatomical localization, genotype, mitotic counts and clinical follow-up. Methylation of a single CpG dinucleotide in the non-CpG island promoter of SPP1 was significantly correlated with shorter disease-free survival. Hypomethylation of this CpG was an independent prognostic parameter in a multivariate analysis compared to anatomical localization, genotype, tumor size and mitotic counts in a cohort of 141 GISTs with clinical follow-up. The epigenetic regulation of SPP1 was confirmed in vitro, and the functional impact of SPP1 protein on tumorigenesis-related signaling pathways was demonstrated. In summary, SPP1 promoter methylation is a novel and independent prognostic parameter in GISTs, and might be helpful in estimating the aggressiveness of GISTs from the intermediate-risk category. © 2014 UICC.

The human genome sequence defines our inherent biological potential; the realization of the biology encoded therein\ud requires knowledge of the function of each gene. Currently, our knowledge in this area is still limited. Several lines of\ud investigation have been used to elucidate the structure and function of the genes in the human genome. Even so, gene\ud prediction remains a difficult task, as the varieties of transcripts of a gene may vary to a great extent. We thus\ud performed an exhaustive integrative characterization of 41,118 full-length cDNAs that capture the gene transcripts as\ud complete functional cassettes, providing an unequivocal report of structural and functional diversity at the gene level.\ud Our international collaboration has validated 21,037 human gene candidates by analysis of high-quality full-length\ud cDNA clones through curation using unified criteria. This led to the identification of 5,155 new gene candidates. It also\ud manifested the most reliable way to control the quality of the cDNA clones. We have developed a human gene\ud database, called the H-Invitational Database (H-InvDB; http://www.h-invitational.jp/). It provides the following:\ud integrative annotation of human genes, description of gene structures, details of novel alternative splicing isoforms,\ud non-protein-coding RNAs, functional domains, subcellular localizations, metabolic pathways, predictions of protein\ud three-dimensional structure, mapping of known single nucleotide polymorphisms (SNPs), identification of polymorphic\ud microsatellite repeats within human genes, and comparative results with mouse full-length cDNAs. The H-InvDB\ud analysis has shown that up to 4% of the human genome sequence (National Center for Biotechnology Information\ud build 34 assembly) may contain misassembled or missing regions. We found that 6.5% of the human gene candidates\ud (1,377 loci) did not have a good protein-coding open reading frame, of which 296 loci are strong candidates for nonprotein-coding\ud RNA genes. In addition, among 72,027 uniquely mapped SNPs and insertions/deletions localized within\ud human genes, 13,215 nonsynonymous SNPs, 315 nonsense SNPs, and 452 indels occurred in coding regions. Together\ud with 25 polymorphic microsatellite repeats present in coding regions, they may alter protein structure, causing\ud phenotypic effects or resulting in disease. The H-InvDB platform represents a substantial contribution to resources\ud needed for the exploration of human biology and pathology

Udgivelsesdato: 2002-Nov Deleted in malignant brain tumors 1 (DMBT1) at 10q25.3-q26.1 has been proposed as a candidate tumor-suppressor gene for brain and epithelial cancer. DMBT1 encodes a multifunctional mucin-like protein presumably involved in epithelial differentiation and protection. The gene consists of highly homologous and repeating exon and intron sequences. This specifically applies to the region coding for the repetitive scavenger receptor cysteine-rich (SRCR) domains and SRCR-interspersed domains (SIDs) that constitutes the major part of the gene. This particular structure may previously have interfered with the delineation of DMBT1 alterations in cancer. Uncovering these, however, is of mechanistic importance. By a combined approach, we conducted a detailed mutational analysis, starting from a panel of 51 tumors, including 46 tumor cell lines and five primary tumors. Alterations in the repetitive region were present in 22/31 (71%) tumors that were investigated in detail. Six tumors showed presumably de novo mutations, among these three with point mutations in combination with a loss of heterozygosity. However, none of the alterations unambiguously would be predicted to lead to an inactivation of DMBT1. We define seven distinct DMBT1 alleles based on variable numbers of tandem repeats (VNTRs). At least 11 tumors exclusively harbored these VNTRs. The data suggest that the SRCR/SID region defines a complex multi-allele system that has escaped previous analyses and that represents the major basis for the variability of DMBT1 in cancer. DMBT1 thus compares to mucins rather than to conventional tumor suppressors.

Cbeta2, a 46 kDa splice variant of the Cbeta isoform, is the largest isoform so far described for catalytic subunits from cAMP-dependent protein kinase in mammals. It differs from Cbeta in the first 15 N-terminal residues which are replaced with a 62-residue domain with no similarity to other known proteins. The Cbeta2 protein was identified in cardiac tissue by MS, microsequencing and C-subunit-isoform-selective antibodies. The Cbeta2 protein has a very low abundance of about 2% of total affinity-purified C subunits from bovine cardiac tissue. This, and the similarity of its biochemical properties to Calpha and Cbeta, are probably some of the reasons why the Cbeta2 protein has escaped detection so far. The abundance of the Cbeta2 protein differs dramatically between tissues, with most protein detected in heart, liver and spleen, and the lowest level in testis. Cbeta2 protein shows kinase activity against synthetic substrates, and is inhibited by the protein kinase inhibitor peptide PKI(5-24). The degree of Cbeta2 removal from tissue extracts by binding to PKI(5-24) depends on the cAMP level, i.e. on the dissociation state of the holoenzyme. Two sites in the protein are phosphorylated: Thr-244 in the activation segment and Ser-385 close to the C-terminus. By affinity purification and immunodetection Cbeta2 was found in cattle, pig, rat, mouse and turkey tissue and in HeLa cells. In the cAMP-insensitive CHO 10260 cell line, which has normal Cbeta but is depleted of Calpha, stable transfection with Cbeta2 restored most of the cAMP-induced morphological changes. Cbeta2 is a ubiquitously expressed protein with characteristic properties of a cAMP-dependent protein kinase catalytic subunit.