36 research outputs found
Symptom-based stratification of patients with primary Sjögren's syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials
Background
Heterogeneity is a major obstacle to developing effective treatments for patients with primary Sjögren's syndrome. We aimed to develop a robust method for stratification, exploiting heterogeneity in patient-reported symptoms, and to relate these differences to pathobiology and therapeutic response.
Methods
We did hierarchical cluster analysis using five common symptoms associated with primary Sjögren's syndrome (pain, fatigue, dryness, anxiety, and depression), followed by multinomial logistic regression to identify subgroups in the UK Primary Sjögren's Syndrome Registry (UKPSSR). We assessed clinical and biological differences between these subgroups, including transcriptional differences in peripheral blood. Patients from two independent validation cohorts in Norway and France were used to confirm patient stratification. Data from two phase 3 clinical trials were similarly stratified to assess the differences between subgroups in treatment response to hydroxychloroquine and rituximab.
Findings
In the UKPSSR cohort (n=608), we identified four subgroups: Low symptom burden (LSB), high symptom burden (HSB), dryness dominant with fatigue (DDF), and pain dominant with fatigue (PDF). Significant differences in peripheral blood lymphocyte counts, anti-SSA and anti-SSB antibody positivity, as well as serum IgG, κ-free light chain, β2-microglobulin, and CXCL13 concentrations were observed between these subgroups, along with differentially expressed transcriptomic modules in peripheral blood. Similar findings were observed in the independent validation cohorts (n=396). Reanalysis of trial data stratifying patients into these subgroups suggested a treatment effect with hydroxychloroquine in the HSB subgroup and with rituximab in the DDF subgroup compared with placebo.
Interpretation
Stratification on the basis of patient-reported symptoms of patients with primary Sjögren's syndrome revealed distinct pathobiological endotypes with distinct responses to immunomodulatory treatments. Our data have important implications for clinical management, trial design, and therapeutic development. Similar stratification approaches might be useful for patients with other chronic immune-mediated diseases.
Funding
UK Medical Research Council, British Sjogren's Syndrome Association, French Ministry of Health, Arthritis Research UK, Foundation for Research in Rheumatology
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Effect of simple amino acid replacements on the biological activity of luteinizing hormone-releasing hormone
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Analogs of luteinizing hormone-releasing hormone containing derivatives of phenylalanine in place of tyrosine
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[35] Solid phase synthesis of luteinizing hormone-releasing hormone and its analogues
The elucidation of the structure of luteinizing hormone–releasing hormone (LH-RH) (II), isolated from both porcine and ovine hypothalami led rapidly to the synthesis of the decapeptide by both classic and solid phase techniques. The natural and synthetic materials also stimulate the release of follicle stimulating hormone (FSH) in animals and human beings. There is considerable interest in establishing structure-activity relationships for this decapeptide and particularly in finding related compounds that might inhibit, instead of stimulate, the release of LH and FSH from the pituitary. This would aid in developing new methods for birth control using antagonistic analogues of LH-RH. The demand for large amounts of pure synthetic LH-RH for extensive studies in laboratory and domestic animals and human beings has resulted in the development in this laboratory of a convenient and reliable synthesis of the hormone by the use of the Merrifield solid phase method. This method has also been utilized with success to synthesize analogues of LH-RH
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Structure-Activity Relationship of LH and FSH Releasing Hormone
During the past few years, several peptide hormones have been purified from hypothalamic tissue, their molecular structures determined and syntheses performed (Schally et al., 1973a). Studies carried out in vitro and in vivo clearly demonstrated that these peptides can selectively stimulate or inhibit the secretion of pituitary hormones from the anterior pituitary gland (Schally et al., 1973a). Careful clinical and veterinary evaluation of these hormones is in progress. It is likely that in the course of the next few years additional hypothalamic hormones will be isolated, identified, and synthesized. The purpose of this chapter is to review the methods of isolation and particularly synthesis of one of these hypothalamic hormones, the LH and FSH releasing hormone (LH-RH/FSH-RH) and to report the latest findings on the structure-activity relationships of this hormone
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Stereoisomers of luteinizing hormone-releasing hormone
Six decapeptide analogs of the luteinizing hormone-releasing hormone (LH-RH) were prepared with the D-isomers of pyroglutamic acid, histidine, tryptophan, tyrosine, leucine, and arginine successively replacing the corresponding L-amino acids of the hormone. [D-pGlu
1]-LH-RH and [D-His
2]-LH-RH had appreciable LH-releasing activities, 8% and 9%, respectively. The remaining analogs were less potent, having the following activities: [D-Trp
3]-LH-RH, 0.1%; [D-Tyr
5]-LH-RH, 0.1%; [D-Leu
7]-LH-RH, 1.0%; [D-Arg
8]-LH-RH, 0.3%
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Solid phase synthesis of growth hormone-release inhibiting factor
The growth hormone-release inhibiting factor (GH-RIF) tetradecapeptide
▪, was prepared by the cyclization of a linear, disulfhydryl peptide intermediate by treatment with potassium ferricyanide. The linear peptide was synthesized by an automated solid-phase technique. The cyclic material inhibited the secretion of radioimmunoassayable growth hormone
in vitro
at doses as low as 0.1 μg. A high molecular weight compound formed during the cyclization reaction and believed to be predominantly dimer also possessed considerable inhibitory activity
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Synthesis and biological properties of [2-L-.beta.-(pyrazolyl-3)alanine]-luteinizing hormone-releasing hormone
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Synthesis of luteinizing hormone-releasing hormone containing tritium-labelled pyroglutamic acid
A method of preparing luteinizing hormone-releasing hormone (LH-RH) pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH
2, by a combination of solid-phase and classical reactions was employed to conveniently synthesize a tritium-labelled hormone by incorporation of 4-[
3H]-pyroglutamic acid into position I of the peptide chain. The tritiated LH-RH possessed a specific radioactivity of 18.3 Ci/mmole and a maximal biological potency