Improved synthesis of 4-[18F]fluoro-m-hydroxyphenethylguanidine using an iodonium ylide precursor

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151961/1/jlcr3791.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151961/2/jlcr3791_am.pd

Binding of [ 3 H]mazindol to cardiac norepinephrine transporters: kinetic and equilibrium studies

The norepinephrine transporter (NET) is the carrier that drives the neuronal norepinephrine uptake mechanism (uptake 1 ) in mammalian hearts. The radioligand [ 3 H]mazindol binds with high affinity to NET. In this study, the kinetics of [ 3 H]mazindol binding to NET were measured using a rat heart membrane preparation. Results from these studies were used to set up saturation binding assays designed to measure cardiac NET densities ( B max ) and competitive inhibition assays designed to measure inhibitor binding affinities ( K I ) for NET. Saturation binding assays measured NET densities in rat, rabbit, and canine hearts. Assay reproducibility was assessed and the effect of NaCl concentration on [ 3 H]mazindol binding to NET was studied using membranes from rat and canine hearts. Specificity of [ 3 H]mazindol binding to NET was determined in experiments in which the neurotoxin 6-hydroxydopamine (6-OHDA) was used to selectively destroy cardiac sympathetic nerve terminals in rats. Competitive inhibition studies measured K I values for several NET inhibitors and substrates. In kinetic studies using rat heart membranes, [ 3 H]mazindol exhibited a dissociation rate constant k off =0.0123±0.0007 min −1 and an association rate constant k on =0.0249±0.0019 nM −1 min −1 . In saturation binding assays, [ 3 H]mazindol binding was monophasic and saturable in all cases. Increasing the concentration of NaCl in the assay buffer increased binding affinity significantly, while only modestly increasing B max . Injections of 6-OHDA in rats decreased measured cardiac NET B max values in a dose-dependent manner, verifying that [ 3 H]mazindol binds specifically to NET from sympathetic nerve terminals. Competitive inhibition studies provided NET inhibitor and substrate K I values consistent with previously reported values. These studies demonstrate the high selectivity of [ 3 H]mazindol binding for the norepinephrine transporter in membrane preparations from mammalian hearts.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46313/1/210_2004_Article_949.pd

The Semantic Web MIDI Tape: An Interface for Interlinking MIDI and Context Metadata

The Linked Data paradigm has been used to publish a large number of musical datasets and ontologies on the Semantic Web, such as MusicBrainz, AcousticBrainz, and the Music Ontology. Recently, the MIDI Linked Data Cloud has been added to these datasets, representing more than 300,000 pieces in MIDI format as Linked Data, opening up the possibility for linking fine-grained symbolic music representations to existing music metadata databases. Despite the dataset making MIDI resources available in Web data standard formats such as RDF and SPARQL, the important issue of finding meaningful links between these MIDI resources and relevant contextual metadata in other datasets remains. A fundamental barrier for the provision and generation of such links is the difficulty that users have at adding new MIDI performance data and metadata to the platform. In this paper, we propose the Semantic Web MIDI Tape, a set of tools and associated interface for interacting with the MIDI Linked Data Cloud by enabling users to record, enrich, and retrieve MIDI performance data and related metadata in native Web data standards. The goal of such interactions is to find meaningful links between published MIDI resources and their relevant contextual metadata. We evaluate the Semantic Web MIDI Tape in various use cases involving user-contributed content, MIDI similarity querying, and entity recognition methods, and discuss their potential for finding links between MIDI resources and metadata

PATH-38. ROSETTE-FORMING GLIONEURONAL TUMOR IS DEFINED BY FGFR1 ACTIVATING ALTERATIONS WITH FREQUENT ACCOMPANYING PI3K AND MAPK PATHWAY MUTATIONS

Abstract BACKGROUND Rosette-forming glioneuronal tumor (RGNT) is an uncommon CNS tumor originally described in the fourth ventricle characterized by a low-grade glial neoplasm admixed with a rosette-forming neurocytic component. METHODS We reviewed clinicopathologic features of 42 patients with RGNT. Targeted next-generation sequencing was performed, and genome-wide methylation profiling is underway. RESULTS The 20 male and 22 female patients had a mean age of 25 years (range 3–47) at time of diagnosis. Tumors were located within or adjacent to the lateral ventricle (n=16), fourth ventricle (15), third ventricle (9), and spinal cord (2). All 31 tumors assessed to date contained FGFR1 activating alterations, either in-frame gene fusion, kinase domain tandem duplication, or hotspot missense mutation in the kinase domain (p.N546 or p.K656). While 7 of these 31 tumors harbored FGFR1 alterations as the solitary pathogenic event, 24 contained additional pathogenic alterations within PI3-kinase or MAP kinase pathway genes: 5 with additional PIK3CA and NF1 mutations, 4 with PIK3CA mutation, 3 with PIK3R1 mutation (one of which also contained focal RAF1 amplification), 5 with PTPN11 mutation (one with additional PIK3R1 mutation), and 2 with NF1 deletion. The other 5 cases demonstrated anaplastic features including hypercellularity and increased mitotic activity. Among these anaplastic cases, 3 harbored inactivating ATRX mutations and two harbored CDKN2A homozygous deletion, in addition to the FGFR1 alterations plus other PI3-kinase and MAP kinase gene mutations seen in those RGNT without anaplasia. CONCLUSION Independent of ventricular location, RGNT is defined by FGFR1 activating mutations or rearrangements, which are frequently accompanied by mutations involving PIK3CA, PIK3R1, PTPN11, NF1, and KRAS. Whereas pilocytic astrocytoma and ganglioglioma are characterized by solitary activating MAP kinase pathway alterations (e.g. BRAF fusion or mutation), RGNT are genetically more complex with dual PI3K-Akt-mTOR and Ras-Raf-MAPK pathway activation. Rare anaplastic examples may show additional ATRX and/or CDKN2A inactivation