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  • 1
    Language: English
    In: Nature methods, 2011-03, Vol.8 (3), p.267-272
    Description: Class I phosphoinositide-3-kinase (PI3K) isoforms generate the intracellular signaling lipid, phosphatidylinositol(3,4,5)trisphosphate (PtdIns(3,4,5)P(3)). PtdIns(3,4,5)P(3) regulates major aspects of cellular behavior, and the use of both genetic and pharmacological intervention has revealed important isoform-specific roles for PI3Ks in health and disease. Despite this interest, current methods for measuring PtdIns(3,4,5)P(3) have major limitations, including insensitivity, reliance on radiolabeling, low throughput and an inability to resolve different fatty-acyl species. We introduce a methodology based on phosphate methylation coupled to high-performance liquid chromatography-mass spectrometry (HPLC-MS) to solve many of these problems and describe an integrated approach to quantify PtdIns(3,4,5)P(3) and related phosphoinositides (regio-isomers of PtdInsP and PtdInsP(2) are not resolved). This methodology can be used to quantify multiple fatty-acyl species of PtdIns(3,4,5)P(3) in unstimulated mouse and human cells (≥10(5)) or tissues (≥0.1 mg) and their increase upon appropriate stimulation.
    Subject(s): Animals ; Cell Line, Tumor ; Cells - chemistry ; Cellular biology ; Chromatography, Liquid - methods ; Fats - chemistry ; Humans ; Kinases ; Lipids ; Liver - chemistry ; Mass spectrometry ; Mass Spectrometry - methods ; Mice ; Molecular biology ; Neutrophils - chemistry ; Phosphatidylinositol Phosphates - analysis ; Scientific method
    ISSN: 1548-7091
    E-ISSN: 1548-7105
    Source: Academic Search Ultimate
    Source: Get It Now
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  • 2
    Language: English
    In: eLife, 2019-02-08, Vol.8
    Description: Decoding the functional connectivity of the nervous system is facilitated by transgenic methods that express a genetically encoded reporter or effector in specific neurons; however, most transgenic lines show broad spatiotemporal and cell-type expression. Increased specificity can be achieved using intersectional genetic methods which restrict reporter expression to cells that co-express multiple drivers, such as Gal4 and Cre. To facilitate intersectional targeting in zebrafish, we have generated more than 50 new Cre lines, and co-registered brain expression images with the Zebrafish Brain Browser, a cellular resolution atlas of 264 transgenic lines. Lines labeling neurons of interest can be identified using a web-browser to perform a 3D spatial search (zbbrowser.com). This resource facilitates the design of intersectional genetic experiments and will advance a wide range of precision circuit-mapping studies.
    Subject(s): Biology ; brain atlas ; Brain mapping ; Brain research ; Cre ; Danio rerio ; Gal4 ; Gene mapping ; imaging ; intersectional genetics ; Laboratories ; Life Sciences & Biomedicine ; Life Sciences & Biomedicine - Other Topics ; Methods ; Nervous system ; Neural circuitry ; Neural networks ; Neuroimaging ; Neuroscience ; Neurosciences ; registration ; Science & Technology ; Tools and Resources ; Zebrafish
    ISSN: 2050-084X
    E-ISSN: 2050-084X
    Source: Web of Science - Science Citation Index Expanded - 2019〈img src="http://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" /〉
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 3
    Language: English
    In: Biochemical journal, 2004-03-15, Vol.378 (Pt 3), p.727-734
    Description: Ubiquitination regulates the stability and/or activity of numerous cellular proteins. The corollary is that de-ubiquitinating enzymes, which 'trim' polyubiquitin chains from specific substrate proteins, play key roles in controlling fundamental cellular activities. Ubiquitin is essential at several stages during the activation of NF-kappaB (nuclear factor kappaB), a central co-ordinator of inflammation and other immune processes. Ubiquitination is known to cause degradation of the inhibitory molecule IkappaBalpha (inhibitor of kappaB). In addition, activation of TRAF (tumour-necrosis-factor-receptor-associated factor) and IKKgamma (IkappaB kinase gamma)/NEMO (NF-kappaB essential modifier) signal adaptors relies on their modification with 'nonclassical' forms of polyubiquitin chains. Ubiquitin also plays a key role in determining cell fate by modulating the stability of numerous pro-apoptotic or anti-apoptotic proteins. The zinc-finger protein A20 has dual functions in inhibiting NF-kappaB activation and suppressing apoptosis. The molecular mechanisms of these anti-inflammatory and cytoprotective effects are unknown. Here we demonstrate that A20 is a de-ubiquitinating enzyme. It contains an N-terminal catalytic domain that belongs to the ovarian-tumour superfamily of cysteine proteases. A20 cleaved ubiquitin monomers from branched polyubiquitin chains linked through Lys48 or Lys63 and bound covalently to a thiol-group-reactive, ubiquitin-derived probe. Mutation of a conserved cysteine residue in the catalytic site (Cys103) abolished these activities. A20 did not have a global effect on ubiquitinated cellular proteins, which indicates that its activity is target-specific. The biological significance of the catalytic domain is unknown.
    Subject(s): Animals ; Catalytic Domain ; Cell Line ; Cell Survival ; DNA-Binding Proteins ; Endopeptidases - chemistry ; Endopeptidases - metabolism ; Humans ; Hydrolysis ; Inflammation - metabolism ; Intracellular Signaling Peptides and Proteins ; Nuclear Proteins ; Polyubiquitin - metabolism ; Proteins - chemistry ; Proteins - metabolism ; Proteins - physiology ; Tumor Necrosis Factor alpha-Induced Protein 3 ; Ubiquitins - metabolism ; Zinc Fingers
    ISSN: 0264-6021
    E-ISSN: 1470-8728
    Source: PubMed Central
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  • 4
    Language: English
    In: Brain (London, England : 1878), 2006-05-02, Vol.129 (7), p.1884-1891
    Description: Oligodendroglial neoplasms with the −1p/−19q genotype are more indolent with longer survival and increased therapeutic responsiveness than those with intact 1p/19q, but the biological basis for these clinical differences is unclear. Recent research suggests that oligodendrogliomas with and without the −1p/−19q genotype may be distinguished by their magnetic resonance imaging (MRI) appearance, suggesting possible differences in growth characteristics. This study examined the relationship between genotype and histological growth patterns of oligodendroglial neoplasms in association with MR imaging characteristics. Tumour imaging features assessed on MRI included sharp-versus-indistinct border, smooth-versus-irregular contour, homogeneous-versus-heterogeneous signal, contrast enhancement and paramagnetic susceptibility effect. Growth patterns (solid : mixed : infiltrative), tumour-margin transitions in cellularity and calcification were determined histopathologically. Allelic imbalance in chromosomes 1p36 and 19q13 was determined. Thirty-three oligodendrogliomas (25 with 1p/19q loss) and 53 oligoastrocytomas (18 with 1p/19q loss) were investigated. Solid, mixed or infiltrative growth patterns were seen in grade II and grade III tumours with or without 1p/19q loss, but infiltrative growth was more common in tumours with intact 1p/19q (χ2: P = 0.029). Grade III tumours were more likely to have a solid growth pattern (χ2: P = 0.046) associated with contrast enhancement (χ2: P = 0.011). Transition in cellularity at the radiological margin did not differ according to genotype. All cases with T1 or T2 signal homogeneity had intact 1p/19q. Tumours with sharp/smooth borders were more likely to have intact 1p/19q than those with indistinct/irregular borders (χ2: P 〈 0.001), but this was not related to histological growth characteristics. This study identified a group of oligodendroglial tumours with intact 1p/19q displaying distinctive MR imaging features that were unrelated to the histopathology characteristics.
    Subject(s): Abridged Index Medicus ; Adult ; Allelic Imbalance ; Biological and medical sciences ; Brain Neoplasms - genetics ; Brain Neoplasms - pathology ; brain tumour ; Chromosomes, Human, Pair 1 - genetics ; Chromosomes, Human, Pair 19 - genetics ; Female ; Genotype ; histopathology ; Humans ; Image Processing, Computer-Assisted - methods ; Investigative techniques, diagnostic techniques (general aspects) ; Magnetic Resonance Imaging - methods ; Male ; Medical sciences ; Middle Aged ; molecular genetics ; MRI ; Nervous system ; Neurology ; Oligodendroglioma - genetics ; Oligodendroglioma - pathology ; Radiodiagnosis. Nmr imagery. Nmr spectrometry ; Tumors of the nervous system. Phacomatoses
    ISSN: 0006-8950
    E-ISSN: 1460-2156
    Source: Alma/SFX Local Collection
    Source: Get It Now
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  • 5
    Language: English
    In: Neuroradiology, 2006, Vol.48 (10), p.703-713
    Description: The biological factors responsible for differential chemoresponsiveness in oligodendroglial tumours with or without the -1p/-19q genotype are unknown, but tumour vascularity may contribute. We aimed to determine whether dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) could distinguish molecular subtypes of oligodendroglial tumour, and examined the relationship between relative cerebral blood volume (rCBV) and outcome following procarbazine, lomustine and vincristine (PCV) chemotherapy. Pretherapy rCBV was calculated and inter- and intraobserver variability assessed. Allelic imbalance in 1p36, 19q13, 17p13, 10p12-15, and 10q22-26 and p53 mutation (exons 5-8) were determined. rCBV was compared with genotype and clinicopathological characteristics (n=37) and outcome following PCV chemotherapy (n=33). 1p/19q loss was seen in 6/9 grade II oligodendrogliomas, 6/14 grade II oligoastrocytomas, 4/4 grade III oligodendrogliomas, and 3/10 grade III oligoastrocytomas. rCBV measurements had good inter- and intraobserver variability, but did not distinguish histology subtype or grade. Tumours with 1p/19q loss had higher rCBV values (Student's t-test P=0.001). Receiver operating characteristic analysis revealed a cut-off of 1.59 for identifying genotype (sensitivity 92%, specificity 76%). Tumours with high and low rCBV showed response to chemotherapy. The -1p/-19q genotype, but not rCBV, was strongly associated with response, progression-free and overall survival following PCV chemotherapy. Tumours with high rCBV and intact 1p/19q were associated with shorter progression-free and overall patient survival than those with intact 1p/19q and low rCBV or high rCBV and 1p/19q loss. rCBV identifies oligodendroglial tumours with 1p/19q loss, but does not predict chemosensitivity. The prognostic significance of rCBV may differ in oligodendroglial tumours with or without the -1p/-19q genotype.
    Subject(s): Adult ; Adult and adolescent clinical studies ; Aged ; Antineoplastic Agents - therapeutic use ; Biochemistry ; Biological and medical sciences ; Blood ; Blood Volume ; Brain ; Brain Neoplasms - diagnosis ; Brain Neoplasms - genetics ; Brain Neoplasms - physiopathology ; Cardiovascular system ; Chemosensitivity ; Diagnostic Neuroradiology ; Genetic aspects ; Genotype ; Genotype & phenotype ; Humans ; Investigative techniques, diagnostic techniques (general aspects) ; Loss of Heterozygosity ; Magnetic Resonance Imaging - methods ; Medical prognosis ; Medical sciences ; Middle Aged ; Miscellaneous ; Mood disorders ; Nervous system ; Oligodendroglial tumour ; Oligodendroglioma - diagnosis ; Oligodendroglioma - genetics ; Oligodendroglioma - physiopathology ; Outcome ; Predictive Value of Tests ; Prospective Studies ; Psychology. Psychoanalysis. Psychiatry ; Psychopathology. Psychiatry ; Radiodiagnosis. Nmr imagery. Nmr spectrometry ; Radiology ; rCBV ; Treatment Outcome ; Tumors
    ISSN: 0028-3940
    E-ISSN: 1432-1920
    Source: Alma/SFX Local Collection
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  • 6
    Language: English
    In: The Journal of biological chemistry, 2003-06-20, Vol.278 (25), p.23180-23186
    Description: A previous report from this laboratory described two novel proteins that have sequence similarity to A20, a negative regulator of NF-κB (Evans, P. C., Taylor, E. R., Coadwell, J., Heyninck, K., Beyaert, R., and Kilshaw, P. J. (2001) Biochem. J . 357, 617–623). One of these molecules, cellular zinc finger anti-NF-κB (Cezanne), a 100-kDa cytoplasmic protein, also suppressed NF-κB. Here we demonstrate that Cezanne is a novel deubiquitinating enzyme, distinct from the two known families of deubiquitinases, Types I and II. We show that Cezanne contains an N-terminal catalytic domain that belongs to the recently discovered ovarian tumor protein (OTU) superfamily, a group of proteins displaying structural similarity to cysteine proteases but having no previously described function. Recombinant Cezanne cleaved ubiquitin monomers from linear or branched synthetic ubiquitin chains and from ubiquitinated proteins. Mutation of a conserved cysteine residue in the catalytic site of the proteolytic domain caused Cezanne to co-precipitate polyubiquitinated cellular proteins. We also provide evidence for an additional ubiquitin binding site in the C-terminal part of the molecule. Our data provide the first demonstration of functional activity among OTU proteins.
    Subject(s): Amino Acid Sequence ; Animals ; Base Sequence ; Binding Sites ; Chlorocebus aethiops ; Cloning, Molecular ; COS Cells ; DNA Primers ; Endopeptidases - chemistry ; Endopeptidases - genetics ; Endopeptidases - metabolism ; Female ; HeLa Cells ; Humans ; Hydrolysis ; Molecular Sequence Data ; Ovarian Neoplasms ; Polymerase Chain Reaction ; Sequence Alignment ; Sequence Homology, Amino Acid ; Tumor Cells, Cultured ; Ubiquitin - metabolism
    ISSN: 0021-9258
    E-ISSN: 1083-351X
    Source: HighWire Press (Free Journals)
    Source: Alma/SFX Local Collection
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  • 7
    Language: English
    In: Journal of neuro-oncology, 2009-07-19, Vol.96 (3), p.385-392
    Description: Purpose Apparent diffusion coefficient (ADC) describes water diffusion within tissues. Previous studies report a negative linear correlation between minimum ADC and tumour cellularity in different types of gliomas, but there are no studies in oligodendroglial tumours. This study evaluated the relationship between ADC and tumour cellularity in oligodendroglial tumours characterized by genotype. Methods ADC was assessed in 17 patients with known 1p/19q status: 3 grade II oligodendrogliomas (OII), 9 grade II oligoastrocytomas (OAII), 5 grade III oligoastrocytomas (OAIII). Regions of interest were placed on ADC maps around tumour margins to generate mean tumour ADC, and over minimum and maximum tumour ADC. Histopathology assessment of tumour cellularity determined minimum, maximum and mean cell density in serial stereotactic biopsies. Results 1p/19q loss was present in 2/3 OII, 5/9 OAII, 2/5 OAIII. Grade III tumours had higher maximum cell density than grade II tumours (17.2 vs. 10.57%: Mann Whitney U ; P   =   0.20 ). Oligoastrocytoma were more likely to have a lower minimum cell density than oligodendrogliomas ( Mann Whitney U ; P   =   0.032 ). There was no relationship between cell density and genotype. There was no linear correlation between mean ADC and mean cell density ( Spearman ’ s rho; r = 0.486: P  = 0.438), minimum ADC and maximum cell density ( Spearman ’ s rho; r = 0.158: P  = 0.660), and maximum ADC and minimum cell density ( Spearman ’ s rho; r = 0.039: P  = 0.985). Conclusions In oligodendroglial tumours there is no relationship between quantitative assessment of cellularity and ADC. This may reflect differences in oligodendroglial tumour biology compared to other gliomas, although the composition of the extracellular matrix may influence ADC more than cellularity.
    Subject(s): Adult ; Aged ; Brain Neoplasms - genetics ; Brain Neoplasms - pathology ; Cancer ; Chromosomes, Human, Pair 1 ; Clinical Study - Patient Study ; Diffusion Magnetic Resonance Imaging ; Female ; Genetic aspects ; Genotype ; Gliomas ; Histochemistry ; Humans ; Loss of Heterozygosity ; Male ; Medicine ; Medicine & Public Health ; Middle Aged ; Neurology ; Oligodendroglioma - genetics ; Oligodendroglioma - pathology ; Oncology ; Oncology, Experimental ; Retrospective Studies ; Statistics, Nonparametric ; Young Adult
    ISSN: 0167-594X
    E-ISSN: 1573-7373
    Source: Alma/SFX Local Collection
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  • 8
    Language: English
    In: Journal of neuro-oncology, 2010-01-10, Vol.99 (1), p.103-113
    Description: DTI-015 (BCNU dissolved in ethanol) utilizes solvent facilitated perfusion (SFP) for intratumoral drug delivery. A phase II clinical trial of DTI-015 and fractionated external beam radiotherapy on newly diagnosed, malignant gliomas investigated early changes in tumour physiology and metabolism, clinical outcome and safety. Pre- and post DTI-015 injection neuro-imaging included computed tomography (CT) cerebral blood flow and volume, glucose and thallium single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI). Clinical status was determined before and after DTI-015, prior to radiotherapy and 3 monthly thereafter until progression (defined by Macdonald criteria). Primary endpoint was radiographic response. Secondary endpoints were progression free (PFS) and overall survival (OS). Twelve patients were enrolled; eight glioblastoma multiforme (GBM), four anaplastic astrocytoma (AA). Three days after DTI-015 injection, mean tumour blood flow (Paired t -test; P  〈 0.001) and blood volume (Paired t -test; P  = 0.001) were significantly reduced. There was a significant decrease in glucose utilization (Paired t -test; P  〈 0.001) and thallium uptake (Paired t -test; P  〈 0.001) at 6 days. Tumour blood volume had a sustained reduction (Paired t -test; P  = 0.001) at 26 days after DTI-015. There were two serious adverse events. Two patients with AA achieved a partial response. Median PFS was 39 weeks for AA and 27 weeks for GBM; median OS for GBM was 47 weeks and 132 weeks for AA. The imaging data forms a biological basis for understanding the effects of high dose BCNU delivered intratumorally by SFP, and suggests early effects on tumour vasculature and metabolism.
    Subject(s): Aged ; Antineoplastic Agents, Alkylating - therapeutic use ; Brain Mapping ; Brain Neoplasms - diagnostic imaging ; Brain Neoplasms - drug therapy ; Brain Neoplasms - radiotherapy ; Cancer ; Carmustine - therapeutic use ; Cerebrovascular Circulation - drug effects ; Clinical Study - Patient Study ; Clinical trials ; CT imaging ; Dextrose ; Disease-Free Survival ; Drug delivery systems ; Drugs ; Female ; Fluorodeoxyglucose F18 ; Glioma - diagnostic imaging ; Glioma - drug therapy ; Glioma - radiotherapy ; Gliomas ; Glucose ; Humans ; Injections, Intramuscular - methods ; Karnofsky Performance Status ; Magnetic Resonance Imaging - methods ; Male ; Medical colleges ; Medicine ; Medicine & Public Health ; Middle Aged ; Neurology ; Oncology ; Oncology, Experimental ; Product development ; Radiotherapy ; Thallium ; Tomography Scanners, X-Ray Computed ; Tomography, Emission-Computed, Single-Photon - methods ; Tomography, X-Ray Computed - methods ; Vehicles
    ISSN: 0167-594X
    E-ISSN: 1573-7373
    Source: Alma/SFX Local Collection
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  • 9
    Language: English
    In: The Journal of biological chemistry, 1996-11-29, Vol.271 (48), p.30561-30570
    Description: Structural studies on the N-linked oligosaccharides of Haemonchus contortus, an economically important nematode that parasitizes domestic ruminants, have revealed core fucosylation of a type not previously observed in any eukaryotic glycoprotein. Mass spectrometric analyses were performed on detergent extracts of homogenized adult H. contortus and on purified H11, a glycoprotein isolated from intestinal brush borders which has been previously shown to be an effective vaccine antigen. The major N-linked glycans identified in the present study have up to three fucose residues attached to their chitobiose cores. The fucoses are found at the 3- and/or 6-positions of the proximal GlcNAc and at the 3-position of the distal GlcNAc. The latter substitution is unique in N-glycans. Most anti-H11 monoclonal antibodies are known to recognize carbohydrate epitopes, and it is possible that the newly discovered multifucosylated core structures are highly immunogenic in this glycoprotein.
    Subject(s): Acetylglucosamine - chemistry ; Animals ; beta-Mannosidase ; Carbohydrate Sequence ; Fucose - chemistry ; Gas Chromatography-Mass Spectrometry ; Glycoproteins - chemistry ; Haemonchus - chemistry ; Helminth Proteins - chemistry ; Mannosidases - metabolism ; Molecular Sequence Data ; Solubility
    ISSN: 0021-9258
    E-ISSN: 1083-351X
    Source: HighWire Press (Free Journals)
    Source: Alma/SFX Local Collection
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  • 10
    Language: English
    In: eLife, 2019-02-08, Vol.8
    Description: Decoding the functional connectivity of the nervous system is facilitated by transgenic methods that express a genetically encoded reporter or effector in specific neurons; however, most transgenic lines show broad spatiotemporal and cell-type expression. Increased specificity can be achieved using intersectional genetic methods which restrict reporter expression to cells that co-express multiple drivers, such as Gal4 and Cre. To facilitate intersectional targeting in zebrafish, we have generated more than 50 new Cre lines, and co-registered brain expression images with the Zebrafish Brain Browser, a cellular resolution atlas of 264 transgenic lines. Lines labeling neurons of interest can be identified using a web-browser to perform a 3D spatial search (zbbrowser.com). This resource facilitates the design of intersectional genetic experiments and will advance a wide range of precision circuit-mapping studies.
    Subject(s): Animals ; Animals, Genetically Modified - genetics ; Brain - physiology ; Brain - ultrastructure ; Brain Mapping - methods ; Cell Lineage - genetics ; DNA-Binding Proteins - genetics ; Gene Expression Regulation - genetics ; Integrases - genetics ; Neuroimaging - methods ; Neurons - physiology ; Neurons - ultrastructure ; Transcription Factors - genetics ; Zebrafish - genetics ; Zebrafish - physiology
    E-ISSN: 2050-084X
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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