Abstract
Objective
To develop and evaluate an adjusted score for the multi-biomarker disease activity (MBDA) test to account for the effects of age, sex and adiposity in patients with RA.
Methods
Two ...models were developed to adjust MBDA score for age, sex and adiposity, using either serum leptin concentration or BMI as proxies for adiposity. Two cohorts were studied. A cohort of 325 781 RA patients who had undergone commercial MBDA testing and had data for age, sex and serum leptin concentration was used for both models. A cohort of 1411 patients from five studies/registries with BMI data was used only for the BMI-adjusted MBDA score. Univariate and multivariate linear regression analyses evaluated the adjusted MBDA scores and conventional clinical measures as predictors of radiographic progression, assessed in terms of modified total Sharp score (ΔmTSS).
Results
Two models were developed, based on findings that MBDA score was higher in females than males and increased with age, leptin concentration and BMI. In pairwise regression analyses, the leptin-adjusted (P = 0.00066) and BMI-adjusted (P = 0.0027) MBDA scores were significant independent predictors of ΔmTSS after adjusting for DAS28-CRP, whereas DAS28-CRP was not, after adjusting for leptin-adjusted (P = 0.74) or BMI-adjusted (P = 0.87) MBDA score. Moreover, the leptin-adjusted MBDA score was a significant predictor of ΔmTSS after adjusting for the BMI-adjusted MBDA score (P = 0.025) or the original MBDA score (0.027), whereas the opposite was not true.
Conclusion
Leptin-adjusted MBDA score significantly adds information to DAS28-CRP and the original MBDA score in predicting radiographic progression. It may offer improved clinical utility for personalized management of RA.
Oligonucleotides (ONs) modified with a 2′-N-(pyren-1-yl)acetyl-2′-amino-α-L-LNA thymine monomer Y flanked on the 3′-side by an abasic site Φ (i.e., YΦ-unit) exhibit unprecedented increases in thermal ...affinity (ΔT m values) toward target strands containing abasic sites (ΔT m per YΦ unit >+33.0 °C in 9-mer duplexes relative to unmodified ONs). Biophysical studies along with force field calculations suggest that the conformationally locked 2-oxo-5-azabicyclo2.2.1heptane skeleton of monomer Y, in concert with the short rigid acetyl linker, efficiently forces the thymine and pyrene moieties to adopt an interplanar distance of ∼3.4 Å. This precisely positions the pyrene moiety in the duplex core void formed by abasic sites (Φ:Φ pair) for optimal π−π overlap. Duplexes with multiple YΦ:AΦ units separated by one base pair are tolerated extraordinarily well, as exemplified by a 13-mer duplex containing four separated YΦ:AΦ units (8 abasic sites distributed over 13 “base pairs”), which exhibit a thermal denaturation temperature of 60.5 °C. The YΦ probes display up to 16-fold increases in fluorescence intensity at 380 nm upon hybridization with abasic target strands, whereby self-assembly of these complex architectures can be easily monitored. This study underlines the potential of N2′-functionalized 2′-amino-α-L-LNA as building blocks in nucleic acid based diagnostics and nanomaterial engineering.
Huntington disease (HD) is a neurodegenerative disease caused by a mutation in the huntingtin (HTT) gene. HTT is a large protein, interacts with many partners and is involved in many cellular ...pathways, which are perturbed in HD. Therapies targeting HTT directly are likely to provide the most global benefit. Thus there is a need for preclinical models of HD recapitulating human HTT genetics. We previously generated a humanized mouse model of HD, Hu97/18, by intercrossing BACHD and YAC18 mice with knockout of the endogenous mouse HD homolog (Hdh). Hu97/18 mice recapitulate the genetics of HD, having two full-length, genomic human HTT transgenes heterozygous for the HD mutation and polymorphisms associated with HD in populations of Caucasian descent. We have now generated a companion model, Hu128/21, by intercrossing YAC128 and BAC21 mice on the Hdh-/- background. Hu128/21 mice have two full-length, genomic human HTT transgenes heterozygous for the HD mutation and polymorphisms associated with HD in populations of East Asian descent and in a minority of patients from other ethnic groups. Hu128/21 mice display a wide variety of HD-like phenotypes that are similar to YAC128 mice. Additionally, both transgenes in Hu128/21 mice match the human HTT exon 1 reference sequence. Conversely, the BACHD transgene carries a floxed, synthetic exon 1 sequence. Hu128/21 mice will be useful for investigations of human HTT that cannot be addressed in Hu97/18 mice, for developing therapies targeted to exon 1, and for preclinical screening of personalized HTT lowering therapies in HD patients of East Asian descent.
Ixekizumab, a high-affinity interleukin-17A (IL-17A) monoclonal antibody, has previously shown efficacy in radiographic axial spondyloarthritis (also known as ankylosing spondylitis). We aimed to ...evaluate the efficacy and safety of ixekizumab, an IL-17 inhibitor, in non-radiographic axial spondyloarthritis. Here, we report the primary results of COAST-X.
COAST-X was a 52-week, randomised, double-blind, placebo-controlled, parallel-group study done at 107 sites in 15 countries in Europe, Asia, North America, and South America. Eligible participants were adults (aged ≥18 years) with active axial spondyloarthritis without definite radiographic sacroiliitis (non-radiographic axial spondyloarthritis), objective signs of inflammation (via MRI or C-reactive protein), and an inadequate response or intolerance to non-steroidal anti-inflammatory drugs (NSAIDs). Patients were randomly assigned (1:1:1) to receive subcutaneous 80 mg ixekizumab every 4 weeks (Q4W) or every 2 weeks (Q2W), or placebo. Changing background medications or switching to open-label ixekizumab Q2W, or both, was allowed after week 16 at investigator discretion. Primary endpoints were Assessment of SpondyloArthritis international Society-40 (ASAS40) response (defined as an improvement of 40% or more and an absolute improvement from baseline of 2 units or more range 0–10 in at least three of the four domains patient global, spinal pain, function, and inflammation without any worsening in the remaining one domain) at weeks 16 and 52. Patients who switched to open-label ixekizumab were imputed as non-responders in logistic regression analysis. This trial is registered with ClinicalTrials.gov, number NCT02757352.
Between Aug 2, 2016, and Jan 29, 2018, 303 patients were enrolled (105 to placebo, 96 to ixekizumab Q4W, and 102 to ixekizumab Q2W). Both primary endpoints were met: ASAS40 at week 16 (ixekizumab Q4W: 34 35% of 96, p=0·0094 vs placebo; ixekizumab Q2W: 41 40% of 102, p=0·0016; placebo: 20 19% of 105) and ASAS40 at week 52 (ixekizumab Q4W: 29 30% of 96, p=0·0045; ixekizumab Q2W: 32 31% of 102, p=0·0037; placebo: 14 13% of 105). 60 (57%) of 104 patients in the placebo group, 63 (66%) of 96 in the ixekizumab Q4W group, and 79 (77%) of 102 in the ixekizumab Q2W group had at least one treatment-emergent adverse event. The most common treatment-emergent adverse events in the ixekizumab groups were nasopharyngitis and injection site reaction. Of the treatment-emergent adverse events of special interest, there was one case of serious infection in the ixekizumab Q4W group. The frequency of serious adverse events was low (four 1% of 302) and similar across the three groups. There were no malignancies or deaths. No new safety signals were identified.
Ixekizumab was superior to placebo for improving signs and symptoms in patients with non-radiographic axial spondyloarthritis at weeks 16 and 52. Reports of adverse events were similar to those of previous ixekizumab studies. Ixekizumab offers a potential therapeutic option for patients with non-radiographic axial spondyloarthritis who had an inadequate response or were intolerant to NSAID therapy.
Eli Lilly and Company.
The synthesis and biophysical evaluation of 3′-Me-α-l-LNA is reported. The synthesis of the nucleoside building block phosphoramidite was accomplished starting from diacetone glucose. The 3′-Me group ...was introduced in the desired configuration by hydride mediated opening of an exocyclic epoxide. Inversion of the 2′-hydroxyl group was achieved by means of an oxidation/reduction sequence followed by cyclization onto a 5′-leaving group to assemble the 2.2.1 ring system. Biophysical evaluation of 3′-Me-α-l-LNA modified oligonucleotides showed good duplex thermal stabilizing properties which were similar to α-l-LNA. Mismatch discrimination experiments revealed that 3′-Me-α-l-LNA possess slightly enhanced discrimination properties for the GU wobble base-pair as compared to related nucleic acid analogs.
Oligonucleotides modified with pyrene-functionalized triazole-linked 2'-deoxyuridines display remarkable hybridization-induced increases in fluorescence emission and enable efficient fluorescent ...discrimination of SNPs via G-specific quenching.
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