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Lupus Sci Med ; 7(1)2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33051264


OBJECTIVE: Long-term extension (LTE) studies of belimumab in SLE do not include a comparator arm, preventing comparisons between belimumab plus standard therapy and standard therapy alone for organ damage accrual. Propensity score matching can be used to match belimumab-treated patients from LTE studies with standard therapy-treated patients from observational cohort studies. This analysis was designed to compare organ damage progression between treatment groups (belimumab plus standard therapy vs standard therapy alone) in patients with SLE with ≥5 years of follow-up, reproducing our previous study with more generalisable data. METHODS: This exploratory post hoc analysis used a heterogeneous population of US and non-US patients receiving monthly intravenous belimumab from pooled BLISS LTE trials (BEL112234/NCT00712933) and standard therapy-treated patients from the Toronto Lupus Cohort. Sixteen clinical variables were selected to calculate the propensity score. RESULTS: The 592 LTE and 381 Toronto Lupus Cohort patients were highly dissimilar across the 16 variables; an adequately balanced sample of 181 LTE and 181 matched Toronto Lupus Cohort patients (mean bias=3.7%) was created using propensity score matching. Belimumab treatment was associated with a smaller increase in Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) over 5 years than standard therapy alone (mean treatment difference=-0.453 (95% CI -0.646 to -0.260); p<0.001). Patients treated with belimumab were 60% less likely to progress to a higher SDI score over any given year of follow-up, compared with standard therapy alone (HR (95% CI) 0.397 (0.275 to 0.572); p<0.001). CONCLUSION: Using propensity score matching, this highly heterogeneous sample was sufficiently matched to the Toronto Lupus Cohort, suggesting that patients treated with intravenous belimumab may have reduced organ damage progression versus standard therapy alone. This analysis of a large and diverse pooled SLE population was consistent with our previously published US-focused study.

J Neurosci ; 24(13): 3421-35, 2004 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-15056722


The stomatogastric nervous system (STNS) is a premiere model for studying modulation of motor pattern generation. Whereas the cellular and network responses to monoamines have been particularly well characterized electrophysiologically, the transduction mechanisms that link the different monoaminergic signals to specific intracellular responses are presently unknown in this system. To begin to elucidate monoaminergic signal transduction in pyloric neurons, we used a bioinformatics approach to predict the existence of 18 monoamine receptors in arthropods, 9 of which have been previously cloned in Drosophila and other insects. We then went on to use the two existing insect databases to clone and characterize the 10th putative arthropod receptor from the spiny lobster, Panulirus interruptus. This receptor is most homologous to the 5-HT2 subtype and shows a dose-dependent response to 5-HT but not to any of the other monoamines present in the STNS. Through a series of pharmacological experiments, we demonstrate that this newly described receptor, 5-HT2betaPan, couples with the traditional G(q) pathway when expressed in HEK293 cells, but not to G(s) or G(i/o). Moreover, it is constitutively active, because the highly conserved DRY motif in transmembrane region 3 has evolved into DRF. Site-directed mutagenesis that reverts the motif back to DRY abolishes this agonist-independent activity. We further demonstrate that this receptor most likely participates in the modulation of stomatogastric motor output, because it is found in neurites in the synaptic neuropil of the stomatogastric ganglion as well as in the axon terminals at identified pyloric neuromuscular junctions.

Neurotransmissores/metabolismo , Palinuridae/fisiologia , Receptores de Neurotransmissores/metabolismo , Receptores 5-HT2 de Serotonina/genética , Receptores 5-HT2 de Serotonina/metabolismo , Motivos de Aminoácidos/fisiologia , Sequência de Aminoácidos , Animais , Aminas Biogênicas/farmacologia , Aminas Biogênicas/fisiologia , Linhagem Celular , Clonagem Molecular , Biologia Computacional/métodos , Sequência Conservada/fisiologia , Sistema Digestório/inervação , Drosophila/genética , Evolução Molecular , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Humanos , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Rede Nervosa/metabolismo , Rede Nervosa/fisiologia , Palinuridae/genética , Proteína Quinase C/metabolismo , Receptores de Neurotransmissores/agonistas , Homologia de Sequência de Aminoácidos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Relação Estrutura-Atividade , Fosfolipases Tipo C/metabolismo