Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 9 de 9
Filter
Add more filters










Database
Language
Publication year range
1.
Diabetologia ; 64(2): 313-324, 2021 02.
Article in English | MEDLINE | ID: mdl-33145642

ABSTRACT

AIMS/HYPOTHESIS: Numerous clinical studies have investigated the anti-CD3ɛ monoclonal antibody otelixizumab in individuals with type 1 diabetes, but limited progress has been made in identifying the optimal clinical dose with acceptable tolerability and safety. The aim of this study was to evaluate the association between dose-response, safety and tolerability, beta cell function preservation and the immunological effects of otelixizumab in new-onset type 1 diabetes. METHODS: In this randomised, single-blind, placebo-controlled, 24 month study, conducted in five centres in Belgium via the Belgian Diabetes Registry, participants (16-27 years old, <32 days from diagnosis of type 1 diabetes) were scheduled to receive placebo or otelixizumab in one of four dose cohorts (cumulative i.v. dose 9, 18, 27 or 36 mg over 6 days; planned n = 40). Randomisation to treatment was by a central computer system; only participants and bedside study personnel were blinded to study treatment. The co-primary endpoints were the incidence of adverse events, the rate of Epstein-Barr virus (EBV) reactivation, and laboratory measures and vital signs. A mixed-meal tolerance test was used to assess beta cell function; exploratory biomarkers were used to measure T cell responses. RESULTS: Thirty participants were randomised/28 were analysed (placebo, n = 6/5; otelixizumab 9 mg, n = 9/8; otelixizumab 18 mg, n = 8/8; otelixizumab 27 mg, n = 7/7; otelixizumab 36 mg, n = 0). Dosing was stopped at otelixizumab 27 mg as the predefined EBV reactivation stopping criteria were met. Adverse event frequency and severity were dose dependent; all participants on otelixizumab experienced at least one adverse event related to cytokine release syndrome during the dosing period. EBV reactivation (otelixizumab 9 mg, n = 2/9; 18 mg, n = 4/8: 27 mg, n = 5/7) and clinical manifestations (otelixizumab 9 mg, n = 0/9; 18 mg, n = 1/8; 27 mg, n = 3/7) were rapid, dose dependent and transient, and were associated with increased productive T cell clonality that diminished over time. Change from baseline mixed-meal tolerance test C-peptide weighted mean AUC0-120 min following otelixizumab 9 mg was above baseline for up to 18 months (difference from placebo 0.39 [95% CI 0.06, 0.72]; p = 0.023); no beta cell function preservation was observed at otelixizumab 18 and 27 mg. CONCLUSIONS/INTERPRETATION: A metabolic response was observed with otelixizumab 9 mg, while doses higher than 18 mg increased the risk of unwanted clinical EBV reactivation. Although otelixizumab can temporarily compromise immunocompetence, allowing EBV to reactivate, the effect is dose dependent and transient, as evidenced by a rapid emergence of EBV-specific T cells preceding long-term control over EBV reactivation. TRIAL REGISTRATION: ClinicalTrials.gov NCT02000817. FUNDING: The study was funded by GlaxoSmithKline. Graphical abstract.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Diabetes Mellitus, Type 1/drug therapy , Insulin Secretion , Insulin-Secreting Cells/metabolism , Adolescent , Adult , C-Peptide/metabolism , Diabetes Mellitus, Type 1/metabolism , Disease Progression , Dose-Response Relationship, Drug , Epstein-Barr Virus Infections/chemically induced , Female , Humans , Latent Infection/chemically induced , Male , Single-Blind Method , Young Adult
2.
Cell Metab ; 31(4): 862-877.e14, 2020 04 07.
Article in English | MEDLINE | ID: mdl-32268117

ABSTRACT

Endothelial cell (EC) metabolism is an emerging target for anti-angiogenic therapy in tumor angiogenesis and choroidal neovascularization (CNV), but little is known about individual EC metabolic transcriptomes. By single-cell RNA sequencing 28,337 murine choroidal ECs (CECs) and sprouting CNV-ECs, we constructed a taxonomy to characterize their heterogeneity. Comparison with murine lung tumor ECs (TECs) revealed congruent marker gene expression by distinct EC phenotypes across tissues and diseases, suggesting similar angiogenic mechanisms. Trajectory inference predicted that differentiation of venous to angiogenic ECs was accompanied by metabolic transcriptome plasticity. ECs displayed metabolic transcriptome heterogeneity during cell-cycle progression and in quiescence. Hypothesizing that conserved genes are important, we used an integrated analysis, based on congruent transcriptome analysis, CEC-tailored genome-scale metabolic modeling, and gene expression meta-analysis in cross-species datasets, followed by in vitro and in vivo validation, to identify SQLE and ALDH18A1 as previously unknown metabolic angiogenic targets.


Subject(s)
Endothelial Cells/metabolism , Lung Neoplasms/metabolism , Macular Degeneration/metabolism , Neovascularization, Pathologic/metabolism , Transcriptome , Animals , Endothelial Cells/cytology , Endothelial Cells/pathology , HEK293 Cells , Human Umbilical Vein Endothelial Cells , Humans , Male , Mice , Mice, Inbred C57BL , Sequence Analysis, RNA , Single-Cell Analysis
4.
Cancer Cell ; 37(1): 21-36.e13, 2020 01 13.
Article in English | MEDLINE | ID: mdl-31935371

ABSTRACT

Heterogeneity of lung tumor endothelial cell (TEC) phenotypes across patients, species (human/mouse), and models (in vivo/in vitro) remains poorly inventoried at the single-cell level. We single-cell RNA (scRNA)-sequenced 56,771 endothelial cells from human/mouse (peri)-tumoral lung and cultured human lung TECs, and detected 17 known and 16 previously unrecognized phenotypes, including TECs putatively regulating immune surveillance. We resolved the canonical tip TECs into a known migratory tip and a putative basement-membrane remodeling breach phenotype. Tip TEC signatures correlated with patient survival, and tip/breach TECs were most sensitive to vascular endothelial growth factor blockade. Only tip TECs were congruent across species/models and shared conserved markers. Integrated analysis of the scRNA-sequenced data with orthogonal multi-omics and meta-analysis data across different human tumors, validated by functional analysis, identified collagen modification as a candidate angiogenic pathway.


Subject(s)
Endothelial Cells/cytology , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Lung Neoplasms/pathology , Neovascularization, Pathologic , Angiogenesis Inhibitors/pharmacology , Animals , Basement Membrane/metabolism , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Cell Movement , Cluster Analysis , Collagen/chemistry , Endothelium, Vascular/metabolism , Female , Humans , Lung Neoplasms/drug therapy , Male , Mice , Phenotype , Single-Cell Analysis , Vascular Endothelial Growth Factor A/metabolism
5.
Curr Diab Rep ; 16(7): 63, 2016 07.
Article in English | MEDLINE | ID: mdl-27168063

ABSTRACT

Autoreactive T cells specific for islet autoantigens develop in type 1 diabetes (T1D) by escaping central as well as peripheral tolerance. The current paradigm for development of islet autoimmunity is just beginning to include the contribution of posttranslationally modified (PTM) islet autoantigens, for which the immune system may be ignorant rather than tolerant. As a result, PTM is the latest promising lead in the quest to understand how the break in peripheral tolerance occurs in T1D. However, it is not completely clear how, where, or when these modifications take place. Currently, only a few PTM antigens have been well-thought-out or identified in T1D, and methods for identifying and characterizing new PTM antigens are rapidly improving. This review will address both reported and potential new sources of modified islet autoantigens and discuss how islet neo-autoantigen generation may contribute to the development and progression of T1D.


Subject(s)
Diabetes Mellitus, Type 1/metabolism , Protein Processing, Post-Translational , Animals , Autoimmunity , Diabetes Mellitus, Type 1/immunology , Histocompatibility Antigens Class I/immunology , Humans , Islets of Langerhans/immunology , Islets of Langerhans/metabolism , Risk Factors
6.
Rheumatology (Oxford) ; 52(6): 1018-21, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23204548

ABSTRACT

OBJECTIVE: To investigate the effect of hyperuricaemia on serum chemokine (C-C motif) ligand 2 (CCL2) levels and blood monocytes in people with gout. METHODS: Whole blood was collected from subjects with a history of acute or chronic gout but not currently experiencing an attack of gout, subjects with asymptomatic hyperuricaemia and healthy individuals with normouricaemia. Serum concentrations of CCL2 were measured by bead array and levels of CD14(+)/CD11b(+) blood monocytes determined by flow cytometry. RESULTS: Subjects with gout and asymptomatic hyperuricaemia had higher serum levels of CCL2 and showed an increase in the percentage of circulating CD14(+) monocytes compared with subjects with normouricaemia. CONCLUSION: Hyperuricaemia causes elevated serum CCL2 levels and increased monocyte recruitment that may be driven by soluble uric acid-induced CCL2 production. Hyperuricaemia may initiate subclinical priming of circulating blood monocytes for adhesion and trafficking during a gout attack.


Subject(s)
Chemokine CCL2/blood , Gout/metabolism , Hyperuricemia/metabolism , Monocytes/metabolism , Uric Acid/blood , Aged , Cell Movement , Female , Gout/blood , Humans , Hyperuricemia/blood , Lipopolysaccharide Receptors/metabolism , Male , Middle Aged
7.
J Org Chem ; 76(21): 9151-6, 2011 Nov 04.
Article in English | MEDLINE | ID: mdl-21958335

ABSTRACT

Bioassay-directed fractionation of an extract of the New Zealand ascidian Aplidium scabellum has afforded the anti-inflammatory secondary metabolite 2-geranyl-6-methoxy-1,4-hydroquinone-4-sulfate (1) and a family of pseudodimeric meroterpenoids scabellones A (2)-D (5). The benzo[c]chromene-7,10-dione scaffold contained within scabellones A-D is particularly rare among natural products. The structures were elucidated by interpretation of NMR data. Scabellone B was also identified as a moderately potent, nontoxic inhibitor of Plasmodium falciparum.


Subject(s)
Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/isolation & purification , Anti-Inflammatory Agents/pharmacology , Antimalarials/chemistry , Antimalarials/isolation & purification , Antimalarials/pharmacology , Benzopyrans/chemistry , Benzopyrans/isolation & purification , Benzopyrans/pharmacology , Plasmodium falciparum/drug effects , Quinones/chemistry , Quinones/isolation & purification , Terpenes/chemistry , Terpenes/isolation & purification , Terpenes/pharmacology , Urochordata/chemistry , Animals , Molecular Structure , New Zealand , Nuclear Magnetic Resonance, Biomolecular , Plasmodium falciparum/chemistry , Quinones/pharmacology
8.
Chembiochem ; 12(17): 2572-6, 2011 Nov 25.
Article in English | MEDLINE | ID: mdl-21990105

ABSTRACT

Going to any length? Trehalose diesters of various chain lengths have been synthesised in order to determine the effect of lipid length on innate immune recognition, as determined by NO and cytokine production by macrophages. In this work, we show that longer lipids (C(20) -C(26)) are required for macrophage activation, with C(22) giving optimal activity.


Subject(s)
Immunity, Innate , Lipids/chemistry , Macrophages/metabolism , Trehalose/chemistry , Animals , Cord Factors/chemistry , Cord Factors/immunology , Cytokines/metabolism , Lipids/immunology , Macrophage Activation , Macrophages/immunology , Male , Mice , Mice, Inbred C57BL , Nitric Oxide/metabolism , Trehalose/immunology
9.
Biomaterials ; 31(16): 4517-29, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20226520

ABSTRACT

Extracellular matrix (ECM) based biomaterials have an established place as medical devices for wound healing and tissue regeneration. In the search for biomaterials we have identified ovine forestomach matrix (OFM), a thick, large format ECM which is biochemically diverse and biologically functional. OFM was purified using an osmotic process that was shown to reduce the cellularity of the ECM and aid tissue delamination. OFM produced using this technique was shown to retain residual basement membrane components, as evidence by the presence of laminin and collagen IV. The collagenous microarchitecture of OFM retained many components of native ECM including fibronectin, glycosaminoglycans, elastin and fibroblast growth factor basic. OFM was non-toxic to mammalian cells and supported fibroblast and keratinocyte migration, differentiation and infiltration. OFM is a culturally acceptable alternative to current collagen-based biomaterials and has immediate clinical applications in wound healing and tissue regeneration.


Subject(s)
Biocompatible Materials/chemistry , Extracellular Matrix/chemistry , Stomach/chemistry , Animals , Biocompatible Materials/metabolism , Cell Adhesion , Cell Differentiation , Collagen/metabolism , Extracellular Matrix/metabolism , Fibroblast Growth Factor 2/metabolism , Humans , Laminin/metabolism , PC12 Cells , Protein Isoforms/metabolism , Rats , Regeneration/physiology , Sheep , Stomach/anatomy & histology
SELECTION OF CITATIONS
SEARCH DETAIL
...