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"Dickson, C"
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The HIV capsid mimics karyopherin engagement of FG-nucleoporins
HIV can infect non-dividing cells because the viral capsid can overcome the selective barrier of the nuclear pore complex and deliver the genome directly into the nucleus
1
,
2
. Remarkably, the intact HIV capsid is more than 1,000 times larger than the size limit prescribed by the diffusion barrier of the nuclear pore
3
. This barrier in the central channel of the nuclear pore is composed of intrinsically disordered nucleoporin domains enriched in phenylalanine–glycine (FG) dipeptides. Through multivalent FG interactions, cellular karyopherins and their bound cargoes solubilize in this phase to drive nucleocytoplasmic transport
4
. By performing an in vitro dissection of the nuclear pore complex, we show that a pocket on the surface of the HIV capsid similarly interacts with FG motifs from multiple nucleoporins and that this interaction licences capsids to penetrate FG-nucleoporin condensates. This karyopherin mimicry model addresses a key conceptual challenge for the role of the HIV capsid in nuclear entry and offers an explanation as to how an exogenous entity much larger than any known cellular cargo may be able to non-destructively breach the nuclear envelope.
Dissection of the nuclear pore complex provides a model in which the HIV capsid enters the nucleus through karyopherin mimicry, a mechanism likely to be conserved across other viruses.
Journal Article
EANM practice guideline/SNMMI procedure standard for dopaminergic imaging in Parkinsonian syndromes 1.0
PurposeThis joint practice guideline or procedure standard was developed collaboratively by the European Association of Nuclear Medicine (EANM) and the Society of Nuclear Medicine and Molecular Imaging (SNMMI). The goal of this guideline is to assist nuclear medicine practitioners in recommending, performing, interpreting, and reporting the results of dopaminergic imaging in parkinsonian syndromes.MethodsCurrently nuclear medicine investigations can assess both presynaptic and postsynaptic function of dopaminergic synapses. To date both EANM and SNMMI have published procedural guidelines for dopamine transporter imaging with single photon emission computed tomography (SPECT) (in 2009 and 2011, respectively). An EANM guideline for D2 SPECT imaging is also available (2009). Since the publication of these previous guidelines, new lines of evidence have been made available on semiquantification, harmonization, comparison with normal datasets, and longitudinal analyses of dopamine transporter imaging with SPECT. Similarly, details on acquisition protocols and simplified quantification methods are now available for dopamine transporter imaging with PET, including recently developed fluorinated tracers. Finally, [18F]fluorodopa PET is now used in some centers for the differential diagnosis of parkinsonism, although procedural guidelines aiming to define standard procedures for [18F]fluorodopa imaging in this setting are still lacking.ConclusionAll these emerging issues are addressed in the present procedural guidelines for dopaminergic imaging in parkinsonian syndromes.
Journal Article
Efficacy and safety of subcutaneous tabalumab, a monoclonal antibody to B-cell activating factor, in patients with systemic lupus erythematosus: results from ILLUMINATE-2, a 52-week, phase III, multicentre, randomised, double-blind, placebo-controlled study
ObjectivesTo evaluate the efficacy and safety of tabalumab, a human IgG4 monoclonal antibody that neutralises membrane and soluble B-cell activating factor (BAFF).MethodsThis randomised, placebo-controlled study enrolled 1124 patients with moderate-to-severe systemic lupus erythematosus (SLE) (Safety of Estrogens in Lupus Erythematosus National Assessment- SLE Disease Activity Index ≥6 at baseline). Patients received standard of care plus subcutaneous study drug, starting with a loading dose (240 mg) at week 0 and followed by 120 mg every 2 weeks (120 Q2W), 120 mg every 4 weeks (120 Q4W) or placebo. Primary endpoint was proportion achieving SLE Responder Index 5 (SRI-5) improvement at week 52.ResultsClinical characteristics were balanced across groups. The primary endpoint was met with 120 Q2W (38.4% vs 27.7%, placebo; p=0.002), but not with the less frequent 120 Q4W regimen (34.8%, p=0.051). Although key secondary endpoints (time to severe flare, corticosteroid sparing and fatigue) were not met, patients treated with tabalumab had greater SRI-5 response rates in a serologically active subset and improvements in more stringent SRI cut-offs, SELENA-SLEDAI, Physician's Global Assessment, anti-double-stranded DNA antibodies, complement, total B cells and immunoglobulins. The incidences of deaths, serious adverse events (AEs), and treatment-emergent AEs were similar in the 120 Q2W, 120 Q4W and placebo groups, but depression and suicidal ideation, albeit rare events, were more commonly reported with tabalumab.ConclusionSRI-5 was met with 120 Q2W and although key secondary endpoints were not met, numerous other secondary endpoints significantly improved in addition to pharmacodynamic evidence of BAFF pathway blockade. The safety profile for tabalumab was similar to placebo, except for depression and suicidality, which were uncommon.Trial registration numberNCT01205438.
Journal Article
Down-Regulating Sphingolipid Synthesis Increases Yeast Lifespan
Knowledge of the mechanisms for regulating lifespan is advancing rapidly, but lifespan is a complex phenotype and new features are likely to be identified. Here we reveal a novel approach for regulating lifespan. Using a genetic or a pharmacological strategy to lower the rate of sphingolipid synthesis, we show that Saccharomyces cerevisiae cells live longer. The longer lifespan is due in part to a reduction in Sch9 protein kinase activity and a consequent reduction in chromosomal mutations and rearrangements and increased stress resistance. Longer lifespan also arises in ways that are independent of Sch9 or caloric restriction, and we speculate on ways that sphingolipids might mediate these aspects of increased lifespan. Sch9 and its mammalian homolog S6 kinase work downstream of the target of rapamycin, TOR1, protein kinase, and play evolutionarily conserved roles in regulating lifespan. Our data establish Sch9 as a focal point for regulating lifespan by integrating nutrient signals from TOR1 with growth and stress signals from sphingolipids. Sphingolipids are found in all eukaryotes and our results suggest that pharmacological down-regulation of one or more sphingolipids may provide a means to reduce age-related diseases and increase lifespan in other eukaryotes.
Journal Article
EANM practice guideline for quantitative SPECT-CT
Abstract PurposeQuantitative SPECT-CT is a modality of growing importance with initial developments in post radionuclide therapy dosimetry, and more recent expansion into bone, cardiac and brain imaging together with the concept of theranostics more generally. The aim of this document is to provide guidelines for nuclear medicine departments setting up and developing their quantitative SPECT-CT service with guidance on protocols, harmonisation and clinical use cases.MethodsThese practice guidelines were written by members of the European Association of Nuclear Medicine Physics, Dosimetry, Oncology and Bone committees representing the current major stakeholders in Quantitative SPECT-CT. The guidelines have also been reviewed and approved by all EANM committees and have been endorsed by the European Association of Nuclear Medicine.ConclusionThe present practice guidelines will help practitioners, scientists and researchers perform high-quality quantitative SPECT-CT and will provide a framework for the continuing development of quantitative SPECT-CT as an established modality.
Journal Article
Triangulation of Hard X-Ray Sources in an X-Class Solar Flare with ASO-S/HXI and Solar Orbiter/STIX
HXI on ASO-S and STIX onboard Solar Orbiter are the first simultaneously operating solar hard X-ray imaging spectrometers. ASO-S’s low Earth orbit and Solar Orbiter’s periodic displacement from the Sun–Earth line enables multi-viewpoint solar hard X-ray spectroscopic imaging analysis for the first time. Here, we demonstrate the potential of this new capability by reporting the first results of 3D triangulation of hard X-ray sources in the SOL2023-12-31T21:55 X5 flare. HXI and STIX observed the flare near the east limb with an observer separation angle of 18°. We triangulated the brightest regions within each source, which enabled us to characterise the large-scale hard X-ray geometry of the flare. The footpoints were found to be in the chromosphere within uncertainty, as expected, while the thermal looptop source was centred at an altitude of 15.1 ± 1 Mm. Given the footpoint separation, this implies a more elongated magnetic-loop structure than predicted by a semi-circular model. These results show the strong diagnostic power of joint HXI and STIX observations for understanding the 3D geometry of solar flares. We conclude by discussing the next steps required to fully exploit their potential.
Journal Article
Epithelioid fibrous histiocytoma: molecular characterization of ALK fusion partners in 23 cases
Epithelioid fibrous histiocytoma is a rare and distinctive cutaneous neoplasm. Most cases harbor ALK rearrangement and show ALK overexpression, which distinguish this neoplasm from conventional cutaneous fibrous histiocytoma and variants. SQSTM1 and VCL have previously been shown to partner with ALK in one case each of epithelioid fibrous histiocytoma. The purpose of this study was to examine a large cohort of epithelioid fibrous histiocytomas by next-generation sequencing to characterize the nature and prevalence of ALK fusion partners. A retrospective archival review was performed to identify cases of epithelioid fibrous histiocytoma (2012–2016). Immunohistochemistry was performed to confirm ALK expression. Targeted next-generation sequencing was applied on RNA extracted from formalin-fixed paraffin-embedded tissue to identify the fusion partners. Twenty-three cases fulfilled inclusion criteria. The mean patient age was 39 years (range, 8–74), there was no sex predilection, and >75% of cases involved the lower extremities. The most common gene fusions were SQSTM1-ALK (N=12; 52%) and VCL-ALK (N=7; 30%); the other four cases harbored novel fusion partners (DCTN1, ETV6, PPFIBP1, and SPECC1L). The pattern of ALK immunoreactivity was usually granular cytoplasmic (N=12; 52%) or granular cytoplasmic and nuclear (N=10; 43%); the case containing an ETV6 fusion partner showed nuclear staining alone. There was no apparent relationship between tumor morphology and the ALK fusion partner. In summary, SQSTM1 and VCL are the most common ALK fusion partners in epithelioid fibrous histiocytoma; DCTN1, ETV6, PPFIBP1, and SPECC1L represent rare fusion partners. The proteins encoded by these genes play diverse roles in scaffolding, cell adhesion, signaling, and transcription (among others) without clear commonalities. These findings expand the oncogenic promiscuity of many of these ALK fusion genes, which drive neoplasia in tumors of diverse lineages with widely varied clinical behavior. This is the first documented account of ETV6-ALK and SPECC1L-ALK translocations in neoplasms.
Journal Article
European multicentre database of healthy controls for 123IFP-CIT SPECT (ENC-DAT): age-related effects, gender differences and evaluation of different methods of analysis
Purpose
Dopamine transporter (DAT) imaging with [
123
I]FP-CIT (DaTSCAN) is an established diagnostic tool in parkinsonism and dementia. Although qualitative assessment criteria are available, DAT quantification is important for research and for completion of a diagnostic evaluation. One critical aspect of quantification is the availability of normative data, considering possible age and gender effects on DAT availability. The aim of the European Normal Control Database of DaTSCAN (ENC-DAT) study was to generate a large database of [
123
I]FP-CIT SPECT scans in healthy controls.
Methods
SPECT data from 139 healthy controls (74 men, 65 women; age range 20 – 83 years, mean 53 years) acquired in 13 different centres were included. Images were reconstructed using the ordered-subset expectation-maximization algorithm without correction (NOACSC), with attenuation correction (AC), and with both attenuation and scatter correction using the triple-energy window method (ACSC). Region-of-interest analysis was performed using the BRASS software (caudate and putamen), and the Southampton method (striatum). The outcome measure was the specific binding ratio (
SBR
).
Results
A significant effect of age on
SBR
was found for all data. Gender had a significant effect on
SBR
in the caudate and putamen for the NOACSC and AC data, and only in the left caudate for the ACSC data (BRASS method). Significant effects of age and gender on striatal
SBR
were observed for all data analysed with the Southampton method. Overall, there was a significant age-related decline in
SBR
of between 4 % and 6.7 % per decade.
Conclusion
This study provides a large database of [
123
I]FP-CIT SPECT scans in healthy controls across a wide age range and with balanced gender representation. Higher DAT availability was found in women than in men. An average age-related decline in DAT availability of 5.5 % per decade was found for both genders, in agreement with previous reports. The data collected in this study may serve as a reference database for nuclear medicine centres and for clinical trials using [
123
I]FP-CIT SPECT as the imaging marker.
Journal Article