P1 gene of Mycoplasma pneumoniae isolated from 2016 to 2019 and relationship between genotyping and macrolide resistance in Hokkaido, Japan

We characterized 515 Mycoplasma pneumoniae specimens in Hokkaido. In 2013 and 2014, the p1 gene type 1 strain, mostly macrolide-resistant, was dominant and the prevalence of macrolide resistance was over 50 %. After 2017, the p1 gene type 2 lineage, mostly macrolide-sensitive, increased and the prevalence of macrolide resistance became 31.0 % in 2017, 5.3 % in 2018 and 16.3 % in 2019.

POS0688 CHARACTERIZATION OF PK/PD OF ANIFROLUMAB IN PATIENTS WITH MODERATE TO SEVERE SLE

Background:In the TULIP-1 and TULIP-2 trials, anifrolumab, a type I interferon (IFN) receptor antibody, at a dosage of 300 mg once every 4 weeks (Q4W), demonstrated consistent median pharmacokinetic (PK) concentrations1 and sustained neutralization of the pharmacodynamic (PD) 21-gene type I IFN gene signature (IFNGS)2–4 in patients with moderate to severe systemic lupus erythematosus (SLE) despite standard therapy.Objectives:To characterize the PK/PD relationship of anifrolumab and to confirm anifrolumab 300 mg provides adequate PD neutralization in IFNGS test–high patients.Methods:This study included IFNGS test–high patients from the phase 3 randomized, placebo-controlled, 52-week TULIP-12 (NCT02446912) and TULIP-23 (NCT02446899) trials of intravenous anifrolumab 150 mg or 300 mg Q4W plus standard therapy. IFNGS test status (high or low) at screening was classified with an analytically validated 4-gene qPCR based test on whole blood.2 PD neutralization was measured with 21-gene type I IFNGS and expressed as a percentage change from baseline.3 For the graphic PK/PD analysis, patients with ≥1 quantifiable serum PK sample and ≥1 PD measurement before discontinuation were categorized depending on Cave (individual predicted average anifrolumab concentration over treatment duration) median and tertiles (T) for anifrolumab 150 mg and 300 mg, respectively. Median PD IFNGS neutralization and medium absolute deviations were compared across Cave subgroups. PK/PD modeling was assessed in patients with ≥1 quantifiable serum PK sample and a baseline and ≥1 postbaseline PD measurement before discontinuation, using a nonlinear mixed-effects model (NONMEM; version 7.3; ICON) to estimate parameters and characterize the PK/PD data. The PD/efficacy analysis included patients with ≥1 postbaseline PD measurement before discontinuation. BILAG-based Combined Lupus Assessment (BICLA) response rates at Week (W)52 were compared across median PD neutralization quartiles (Q) for pooled anifrolumab 300 mg and 150 mg groups.Results:The PK/PD graphic analysis included 654 IFNGS test–high patients (placebo [n=293]; anifrolumab 150 mg [n=72] or 300 mg [n=289]). Cave was generally higher with anifrolumab 300 mg (µg/mL, TULIP-1: T1 <32, T2 32–<44.3, T3 ≥44.3; TULIP-2: T1 <32.4, T2 32.4–<47.9, T3 ≥47.9) than with anifrolumab 150 mg (median 11.5 µg/mL); overlap between anifrolumab 300 mg and 150 mg Cave subgroups was small owing to nonlinearity. Anifrolumab 300 mg elicited rapid (by W44) and sustained median PD neutralization >80%, vs a lower and delayed PD neutralization (median >50% at W52) with anifrolumab 150 mg, and minimal PD neutralization with placebo. The median PD neutralization increased with higher Cave subgroups, plateauing at ~90% at W12–W52. All anifrolumab 300 mg Cave tertiles had a median PD neutralization ~80%; however, the variability was greater in the lowest Cave tertiles vs higher Cave tertiles across trials (Figure 1). The PK/PD modeling, which included 646 IFNGS test–high patients (placebo [n=289], anifrolumab 150 mg [n=70] or 300 mg [n=287]), gave an IC80 estimate of 3.88 μg/mL. The median W24 (study midpoint) Ctrough was higher with anifrolumab 300 mg vs 150 mg (15.6 vs 0.2 μg/mL); thus, the W24 Ctrough exceeded the IC80 in a higher proportion of patients treated with anifrolumab 300 mg vs 150 mg (~83% vs ~27%). The PD/efficacy analysis included 341 patients who received anifrolumab. Higher median percentage PD neutralization quartiles (Q1 <51.7%, Q2 51.7%–85.3%, Q3 85.3%–92.6%, Q4 >92.6%) were associated with higher W52 BICLA response rates (Q1 37.6%, Q2 49.4%, Q3 51.8%, Q4 58.1%).Conclusion:In TULIP-1 and TULIP-2, anifrolumab 300 mg yielded higher anifrolumab Cave vs 150 mg. High Cave was associated with rapid (W44–W12), substantial, and sustained PD neutralization of the 21-gene IFNGS in IFNGS test–high patients, which in turn was associated with higher efficacy.References:[1]Kuruvilla D. Poster 360, AAPS 2020.[2]Furie RA. Lancet Rheumatol. 2019;1:e208–19.[3]Morand EF. N Engl J Med. 2020;382:211–21.[4]Furie R. Arthritis Rheumatol. 2017;69:379–86.Acknowledgements:Writing assistance by Matilda Shackley, MPhil, of JK Associates Inc., part of Fishawack Health. This study was sponsored by AstraZeneca.Disclosure of Interests:Yen Lin Chia Employee of: AstraZeneca, Raj Tummala Employee of: AstraZeneca, Tu Mai Employee of: Genentech, Tomas Rouse Employee of: AstraZeneca, Wendy White Employee of: AstraZeneca, Eric F. Morand Speakers bureau: AstraZeneca, Consultant of: AstraZeneca, Grant/research support from: AstraZeneca, Richard Furie Consultant of: AstraZeneca, Grant/research support from: AstraZeneca

Expression of AhATL1, an ABA Transport Factor Gene from Peanut, Is Affected by Altered Memory Gene Expression Patterns and Increased Tolerance to Drought Stress in Arabidopsis

Arachis hypogaea abscisic acid transporter like-1 (AhATL1) modulates abscisic acid (ABA) sensitivity by specifically influencing the importing of ABA into cells, and is a key player in plant stress responses. However, there is limited information on ABA transporters in crops. In this study, we found that the level of AhATL1 expression and AhATL1 distribution increased more rapidly in the second drought (D2) compared with in the first drought (D1). Compared with the first recovery (R1), the AhATL1 expression level and ABA content remained at a higher level during the second recovery (R2). The heterologous overexpression of AhATL1 in Arabidopsis changed the expression pattern of certain memory genes and changed the post response gene type into the memory gene type. Regarding the proline and water content of Col (Arabidopsis thaliana L. Heynh., Col-0), atabcg22, and AhATL1-OX during drought training, the second drought (D2) was more severe than the first drought (D1), which was more conducive to maintaining the cell osmotic balance and resisting drought. In summary, drought stress memory resulted in a rapid increase in the AhATL1 expression and AhATL1 distribution level, and then raised the endogenous ABA content and changed the post response gene type into the memory gene type, which enhanced the drought resistance and recovery ability.

A modified Ising model of Barabási–Albert network with gene-type spins

The central question of systems biology is to understand how individual components of a biological system such as genes or proteins cooperate in emerging phenotypes resulting in the evolution of diseases. As living cells are open systems in quasi-steady state type equilibrium in continuous exchange with their environment, computational techniques that have been successfully applied in statistical thermodynamics to describe phase transitions may provide new insights to the emerging behavior of biological systems. Here we systematically evaluate the translation of computational techniques from solid-state physics to network models that closely resemble biological networks and develop specific translational rules to tackle problems unique to living systems. We focus on logic models exhibiting only two states in each network node. Motivated by the apparent asymmetry between biological states where an entity exhibits boolean states i.e. is active or inactive, we present an adaptation of symmetric Ising model towards an asymmetric one fitting to living systems here referred to as the modified Ising model with gene-type spins. We analyze phase transitions by Monte Carlo simulations and propose a mean-field solution of a modified Ising model of a network type that closely resembles a real-world network, the Barabási–Albert model of scale-free networks. We show that asymmetric Ising models show similarities to symmetric Ising models with the external field and undergoes a discontinuous phase transition of the first-order and exhibits hysteresis. The simulation setup presented herein can be directly used for any biological network connectivity dataset and is also applicable for other networks that exhibit similar states of activity. The method proposed here is a general statistical method to deal with non-linear large scale models arising in the context of biological systems and is scalable to any network size.