scholarly journals MO072APABETALONE DOWNREGULATES FIBROTIC, INFLAMMATORY AND CALCIFIC PROCESSES IN RENAL MESANGIAL CELLS WHICH MAY CONTRIBUTE TO REDUCED CARDIAC EVENTS OBSERVED IN CKD PATIENTS

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Dean Gilham ◽  
Li Fu ◽  
Brooke Rakai ◽  
Sylwia Wasiak ◽  
Laura Tsujikawa ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alkaline Phosphatase ◽  
Mesangial Cells ◽  
Z Score ◽  
Rna Seq ◽  
Cardiac Events ◽  
Kidney Dysfunction ◽  
Phase 3 ◽  
Go Enrichment ◽  
Tgf Β1

Abstract Background and Aims Major adverse cardiac events (MACE) remain a leading cause of mortality in chronic kidney disease (CKD). Apabetalone is an orally available inhibitor of bromodomain & extraterminal (BET) proteins – epigenetic readers that modulate gene expression involved in fibrosis, inflammation and calcification. In the phase 3 BETonMACE trial, apabetalone treatment was associated with reduction in MACE in the subpopulation with CKD (eGFR < 60 mL/min/1.73m2; HR 0.50 95% CI 0.26,0.96 p=0.04]) implying favorable effects of apabetalone on cellular responses along the kidney-heart axis. This study examines effects of apabetalone on primary human renal mesangial cells (HRMCs) in culture on fibrosis, inflammation, reactive oxygen species (ROS) and calcification pathways that contribute to renal pathology. Method HRMCs from donors without kidney dysfunction were stimulated with TGF-β1 or lipopolysaccharide (LPS) ± 1-25µM apabetalone, 0.15-0.5µM JQ1 or 0.1µM MZ1 (BET inhibitors [BETi] with chemical scaffolds different than apabetalone). Gene expression was measured by real-time PCR and RNA-seq. Smooth muscle actin (α-SMA) was examined by immunofluorescence microscopy, and alkaline phosphatase enzyme activity in a biochemical assay. RNA-seq from TGF-β1 treated HRMC ± BETi was evaluated by Gene Ontology (GO) Enrichment and Ingenuity Pathway Analysis (IPA). Results TGF-β1 is a pro-fibrotic cytokine that activates HRMC to a fibroblast-like state which over-produces extracellular matrix (ECM). Apabetalone dose dependently suppressed TGF-β1 induced gene expression of (a) α-SMA, a marker of fibrotic activation, up to 90% p<0.001 and de novo α-SMA protein production (b) fibronectin, a key ECM component, up to 44% p<0.001 (c) NADPH oxidase 4 (NOX4), involved in production of pro-fibrotic ROS, up to 82% p<0.001 (d) tissue non-specific alkaline phosphatase (TNALP), associated with reduced glomerular function & extracellular calcification, up to 96% as well as TNALP enzyme activity up to 96% p<0.001. An inhibitor of TGF-β receptors reduced or abolished TGF-β1 responses, indicating the expected signal transduction pathways mediated its downstream effects. Apabetalone dose dependently opposed LPS stimulated expression of inflammatory genes: IL6 up to 94%, IL1B up to 95% & PTGS2 (COX2) up to 94% p<0.001, suggesting downregulation of inflammatory processes. In all studies, JQ1 and / or MZ1 had similar activity as apabetalone, confirming on-target BETi effects. In GO Enrichment analysis of RNA-seq from TGF-β1 stimulated HRMCs, multiple gene sets associated with ECM were in the top 20 affected by BETi, supporting anti-fibrotic properties. IPA predicted NfkB-RelA and NFkB (complex) were upstream regulators inhibited by apabetalone, indicating suppression of NF-kB mediated inflammation. IPA also predicted apabetalone activated canonical pathways of glucose utilization & tolerance of ROS production, including Oxidative Phosphorylation (z-score 5.7, p<0.01 at 25µM; z-score 3.5, p>0.05 at 5µM) and NRF2-Mediated Oxidative Stress Response (z score 2.3, p<0.001 at 25µM; z-score 1.6, p<0.001 at 5µM). PGC-1α, a key upstream regulator of the Oxidative Phosphorylation pathway, was also predicted to be activated by apabetalone (z score 4.2, p<0.001 at 25µM; z-score 2.3, p<0.001 at 5µM). These changes in energy metabolism pathways may allow HRMC to cope with elevated glucose. Conclusion Apabetalone downregulated responses to TGF-β1 or LPS in HRMCs that promote fibrotic, inflammatory and calcific processes which exacerbate kidney dysfunction. Changes in energy metabolism pathways predicted apabetalone facilitates adaptation to high glucose in the kidney. Together, our results provide mechanistic insight into reductions in MACE in CKD patients receiving apabetalone in the phase 3 BETonMACE trial. The effect of apabetalone on MACE in patients with diabetes and CKD will be further evaluated in the upcoming BETonMACE2 trial.

scholarly journals Complex fibroblast response to glucocorticoids may underlie variability of clinical efficacy in the vocal folds

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Ryosuke Nakamura ◽  
Shigeyuki Mukudai ◽  
Renjie Bing ◽  
Michael J. Garabedian ◽  
Ryan C. Branski
Keyword(s):  
Gene Expression ◽  
Transforming Growth Factor ◽  
Regulation Of Gene Expression ◽  
Vocal Folds ◽  
Global Changes ◽  
Rna Seq ◽  
Fibrotic Response ◽  
Group A ◽  
Tgf Β1 ◽  
Nuclear Receptor Subfamily

AbstractSimilar to the hypertrophic scar and keloids, the efficacy of glucorticoids (GC) for vocal fold injury is highly variable. We previously reported dexamethasone enhanced the pro-fibrotic effects of transforming growth factor (TGF)-β as a potential mechanism for inconsistent clinical outcomes. In the current study, we sought to determine the mechanism(s) whereby GCs influence the fibrotic response and mechanisms underlying these effects with an emphasis on TGF-β and nuclear receptor subfamily 4 group A member 1 (NR4A1) signaling. Human VF fibroblasts (HVOX) were treated with three commonly-employed GCs+ /-TGF-β1. Phosphorylation of the glucocorticoid receptor (GR:NR3C1) and activation of NR4A1 was analyzed by western blotting. Genes involved in the fibrotic response, including ACTA2, TGFBR1, and TGFBR2 were analyzed by qPCR. RNA-seq was performed to identify global changes in gene expression induced by dexamethasone. GCs enhanced phosphorylation of GR at Ser211 and TGF-β-induced ACTA2 expression. Dexamethasone upregulated TGFBR1, and TGFBR2 in the presence of TGF-β1 and increased active NR4A1. RNA-seq results confirmed numerous pathways, including TGF-β signaling, affected by dexamethasone. Synergistic pro-fibrotic effects of TGF-β were observed across GCs and appeared to be mediated, at least partially, via upregulation of TGF-β receptors. Dexamethasone exhibited diverse regulation of gene expression including NR4A1 upregulation consistent with the anti-fibrotic potential of GCs.

scholarly journals Transcriptome-wide analysis of microRNA-mRNA correlations in unperturbed tissue transcriptomes identifies microRNA targeting determinants.

2021 ◽  
Author(s):  
Juan Manuel Trinidad ◽  
Rafael Sebastian Fort ◽  
Guillermo Trinidad ◽  
Beatriz Garat ◽  
Maria A Duhagon
Keyword(s):  
Gene Expression ◽  
Small Rna ◽  
Current Knowledge ◽  
Gc Content ◽  
Sequence Motif ◽  
Z Score ◽  
Rna Seq ◽  
Microrna Target ◽  
Candidate Sequence ◽  
Interaction Sites

MicroRNAs are small RNAs that regulate gene expression through complementary base pairing with their target mRNAs. Given the small size of the pairing region and the large number of mRNAs that each microRNA can control, the identification of biologically relevant targets is difficult. Since current knowledge of target recognition and repression has mainly relied on in vitro studies, we sought to determine if the interrogation of gene expression data of unperturbed tissues could yield new insight into these processes. The transcriptome-wide repression at the microRNA-mRNA canonical interaction sites (seed and 3'-supplementary region, identified by sole base complementarity) was calculated as a normalized Spearman correlation (Z-score) between the abundance of the transcripts in the PRAD-TCGA tissues (RNA-seq and small RNA-seq data of 546 samples). Using the repression values obtained we confirmed established properties or microRNA targeting efficacy, such as the preference for gene regions (3'UTR>CDS>5'UTR), the proportionality between repression and seed length (6mer<7mer<8mer) and the contribution to the repression exerted by the supplementary pairing at 13-16nt of the microRNA. Our results suggest that the 7mer-m8 seed could be more repressive than the 7mer-A1, while they have similar efficacy when they interact using the 3'-supplementary pairing. Strikingly, the 6mer+suppl sites yielded normalized Z-score of repression similar to the sole 7mer-m8 or 7mer-A1 seeds, which raise awareness of its potential biological relevance. We then used the approach to further characterize the 3'-supplementary pairing, using 39 microRNAs that hold repressive 3'-supplementary interactions. The analysis of the bridge between seed and 3'-supplementary pairing site confirmed the optimum +1 offset previously evidenced, but higher offsets appear to hold similar repressive strength. In addition, they show a low GC content at position 13-16, and base preferences that allow the selection of a candidate sequence motif. Overall, our study demonstrates that transcriptome-wide analysis of microRNA-mRNA correlations in large, matched RNA-seq and small-RNA-seq data has the power to uncover hints of microRNA targeting determinants operating in the in vivo unperturbed set. Finally, we made available a bioinformatic tool to analyze microRNA-target mRNA interactions using our approach.

scholarly journals Regulation of TGF-β1/MAPK-mediated PAI-1 gene expression by the actin cytoskeleton in human mesangial cells

2007 ◽  
Vol 313 (6) ◽  
pp. 1240-1250 ◽  
Author(s):  
Chen Yang ◽  
Keyur Patel ◽  
Pamela Harding ◽  
Andrey Sorokin ◽  
William F. Glass
Keyword(s):  
Gene Expression ◽  
Actin Cytoskeleton ◽  
Mesangial Cells ◽  
Human Mesangial Cells ◽  
Tgf Β1 ◽  
Pai 1

scholarly journals AP-1 Proteins Mediate Hyperglycemia-Induced Activation of the Human TGF-β1 Promoter in Mesangial Cells

2000 ◽  
Vol 11 (11) ◽  
pp. 2007-2016
Author(s):  
CORA WEIGERT ◽  
ULRICH SAUER ◽  
KATRIN BRODBECK ◽  
ANDREAS PFEIFFER ◽  
HANS U. HÄRING ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
High Glucose ◽  
Binding Sites ◽  
Promoter Activity ◽  
Mesangial Cells ◽  
Luciferase Reporter ◽  
Kinase C ◽  
Tgf Β1

Abstract. Hyperglycemia-induced overproduction of the prosclerotic cytokine transforming growth factor-β1 (TGF-β1) has been implicated in the pathogenesis of diabetic nephropathy. Because high glucose and phorbol esters (PMA) increase TGF-β1 mRNA levels in mesangial cells, this study was designed to characterize these effects on the human TGF-β1 promoter activity. With the use of luciferase reporter gene constructs containing TGF-β1 5′-flanking sequence (from -453 to +11 bp) transfected into mesangial cells, it was found that 30 mM glucose induced a nearly twofold increase in TGF-β1 promoter activity after 24 h of incubation in human and porcine mesangial cells. Stimulation by PMA was more effective (2.3-fold). Mutagenesis in either one of the two or both activating protein-1 (AP-1) binding sites abolished the high glucose and the PMA effect. Furthermore, addition of the AP-1 inhibitor curcumin obliterated the glucose response. Corresponding experiments revealed that the transcription factor stimulating protein 1 was not involved in mediating the glucose effect. The high glucose-induced TGF-β1 promoter activation was also prevented by inhibitors of protein kinase C and p38 mitogen-activated proteinkinase. Electrophoretic mobility shift assays with oligonucleotides containing one of the two AP-1 binding sites showed that glucose treatment markedly enhanced the binding activity of nuclear proteins of mesangial cells, particularly to box B. Supershift assays demonstrated that JunD and c-Fos were present in the protein-DNA complexes under control and hyperglycemic conditions. The functional and structural results show that glucose regulates human TGF-β1 gene expression through two adjacent AP-1 binding sites and gives rise to the involvement of protein kinase C and p38 mitogen-activated proteinkinase in hyperglycemia-induced TGF-β1 gene expression.

scholarly journals SO078APABETALONE, A BROMODOMAIN AND EXTRA-TERMINAL (BET) PROTEIN INHIBITOR, REDUCES ALKALINE PHOSPHATASE IN CVD PATIENTS, IN MICE, AND IN CELL CULTURE SYSTEMS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Dean Gilham ◽  
Laura Tsujikawa ◽  
Sylwia Wasiak ◽  
Ravi Jahagirdar ◽  
Li Fu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Culture ◽  
Clinical Trials ◽  
Alkaline Phosphatase ◽  
Endothelial Cells ◽  
Enzyme Activity ◽  
Hepg2 Cells ◽  
Phase 2 ◽  
Phase 3 ◽  
Protein Levels

Abstract Background and Aims Elevated serum alkaline phosphatase (ALP) independently predicts major adverse cardiac events (MACE) by contributing to vascular calcification and endothelial dysfunction arising in chronic kidney disease (CKD) and cardiovascular disease (CVD). Apabetalone is an orally active inhibitor of bromodomain and extraterminal (BET) proteins – epigenetic readers that modulate gene expression involved in vascular inflammation and calcification. Here we examined apabetalone’s effects on ALP post-hoc in recent clinical trials, then performed mechanistic studies into apabetalone’s impact on tissue non-specific ALP (TNALP) expression in mice and cell culture. Method Serum ALP was determined in CVD patients in phase 2 trials (3 month ASSERT and 6 month SUSTAIN & ASSURE) and in the phase 3 BETonMACE CVD outcomes trial, including subpopulations with CKD (eGFR&lt;60 mL/min/1.73m2). Apabetalone’s effect on expression of TNALP (gene symbol ALPL) was examined in mice, cultured primary human hepatocytes (PHH), HepaRG, HepG2, vascular smooth muscle cells (VSMCs), and vascular endothelial cells by real-time PCR. TNALP protein levels were assessed by immunoblots and flow cytometry. ALP enzyme activity was measured in enzymatic assays. Results In phase 2 trials, baseline serum ALP independently predicted MACE (hazard ratio [HR] 1.6, 95% CI 1.2-2.2, p=0.001). In the 3 month ASSERT trial, apabetalone dose dependently reduced serum ALP (p&lt;0.001 vs placebo). Prominent reductions in ALP were apparent in patients on apabetalone (n=331) vs placebo (n=166) in combined analysis of the ASSURE & SUSTAIN trials (median % change -11 vs -3.2; p&lt;0.001). In the subset with CKD, patients on apabetalone (n=69) had greater reduction in serum ALP than placebo (n=22; p=0.008). Strikingly, ALP reductions in phase 2 correlated with reduction in MACE (HR 0.58, 95% CI 0.44-0.77, p&lt;0.001). Consistent with phase 2, BETonMACE saw serum ALP reduced by 6.8 U/L with apabetalone (n=1082) vs placebo (n=1070; p&lt;0.001) at 24 weeks. At the conclusion of BETonMACE, fewer MACE occurred in the CKD subgroup with apabetalone (n=124) vs placebo (n=164; HR 0.50 95% CI 0.26-0.96 p=0.032). Neither apabetalone nor statins that control low-density lipoprotein cholesterol inhibited recombinant TNALP enzyme activity, implying that decreased serum ALP activity in patients reflected reduction in TNALP production rather than inhibition of the enzyme. Liver-derived TNALP accounts for ≈50% of circulating ALP. In the liver of mice on high fat diet, apabetalone or JQ1 (BET inhibitors with different chemical scaffolds) reduced Alpl mRNA (p&lt;0.001) with corresponding trends in TNALP activity. In PHH, HepaRG, & HepG2 cells, apabetalone dose dependently suppressed ALPL expression by 60-80%. In HepG2 cells, apabetalone reduced TNALP protein (&gt;55%, p&lt;0.001), enzyme activity (&gt; 40%; p&lt;0.001), and % of TNALP positive cells (15-30%; p&lt;0.001). MZ1, which promotes degradation of BET proteins, downregulated ALPL / TNALP similar to apabetalone. In VSMCs, apabetalone or JQ1 suppressed ALPL gene expression, TNALP protein levels, and enzyme activity, leading to decreases in extracellular calcium deposition. In addition, apabetalone downregulated ALPL expression in human aortic, umbilical vein, and brain microvascular endothelial cells by 50-70%. Conclusion Apabetalone lowers serum ALP in clinical trials, which is consistent with reduced hepatic production of TNALP - the most abundant ALP isoform. Further, apabetalone downregulates ALPL gene expression in vascular cell types while reducing calcification. Together, BET-dependent epigenetic modulation of ALP by apabetalone can affect several pathogenetic processes, and thereby improve cardiovascular outcomes. This study provides insights to the CVD event reductions observed in the CKD subpopulation in the BETonMACE Phase 3 trial.

scholarly journals Rewired Pathways and Disrupted Pathway Crosstalk in Schizophrenia Transcriptomes by Multiple Differential Coexpression Methods

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 665
Author(s):  
Hui Yu ◽  
Yan Guo ◽  
Jingchun Chen ◽  
Xiangning Chen ◽  
Peilin Jia ◽  
...  
Keyword(s):  
Gene Expression ◽  
Focal Adhesion ◽  
Biological Pathways ◽  
Postmortem Brain ◽  
Rna Seq ◽  
Hub Genes ◽  
Differential Coexpression ◽  
Pathway Crosstalk ◽  
Microarray Datasets ◽  
Transcriptomic Studies

Transcriptomic studies of mental disorders using the human brain tissues have been limited, and gene expression signatures in schizophrenia (SCZ) remain elusive. In this study, we applied three differential co-expression methods to analyze five transcriptomic datasets (three RNA-Seq and two microarray datasets) derived from SCZ and matched normal postmortem brain samples. We aimed to uncover biological pathways where internal correlation structure was rewired or inter-coordination was disrupted in SCZ. In total, we identified 60 rewired pathways, many of which were related to neurotransmitter, synapse, immune, and cell adhesion. We found the hub genes, which were on the center of rewired pathways, were highly mutually consistent among the five datasets. The combinatory list of 92 hub genes was generally multi-functional, suggesting their complex and dynamic roles in SCZ pathophysiology. In our constructed pathway crosstalk network, we found “Clostridium neurotoxicity” and “signaling events mediated by focal adhesion kinase” had the highest interactions. We further identified disconnected gene links underlying the disrupted pathway crosstalk. Among them, four gene pairs (PAK1:SYT1, PAK1:RFC5, DCTN1:STX1A, and GRIA1:MAP2K4) were normally correlated in universal contexts. In summary, we systematically identified rewired pathways, disrupted pathway crosstalk circuits, and critical genes and gene links in schizophrenia transcriptomes.

scholarly journals Mitochondrial Mistranslation in Brain Provokes a Metabolic Response Which Mitigates the Age-Associated Decline in Mitochondrial Gene Expression

2021 ◽  
Vol 22 (5) ◽  
pp. 2746
Author(s):  
Dimitri Shcherbakov ◽  
Reda Juskeviciene ◽  
Adrián Cortés Sanchón ◽  
Margarita Brilkova ◽  
Hubert Rehrauer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Metabolic Response ◽  
Mitochondrial Gene ◽  
Tca Cycle ◽  
Brain Mitochondria ◽  
Mitochondrial Gene Expression ◽  
Rna Seq ◽  
The Tca Cycle ◽  
Neurological Phenotype

Mitochondrial misreading, conferred by mutation V338Y in mitoribosomal protein Mrps5, in-vivo is associated with a subtle neurological phenotype. Brain mitochondria of homozygous knock-in mutant Mrps5V338Y/V338Y mice show decreased oxygen consumption and reduced ATP levels. Using a combination of unbiased RNA-Seq with untargeted metabolomics, we here demonstrate a concerted response, which alleviates the impaired functionality of OXPHOS complexes in Mrps5 mutant mice. This concerted response mitigates the age-associated decline in mitochondrial gene expression and compensates for impaired respiration by transcriptional upregulation of OXPHOS components together with anaplerotic replenishment of the TCA cycle (pyruvate, 2-ketoglutarate).

scholarly journals OP0021 IDENTIFICATION OF DIFFERENTIALLY EXPRESSED GENES IN EARLY RHEUMATOID ARTHRITIS PATIENTS RESPONDING TO TOCILIZUMAB

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 12.2-12
Author(s):  
I. Muller ◽  
M. Verhoeven ◽  
H. Gosselt ◽  
M. Lin ◽  
T. De Jong ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
T Cells ◽  
Gene Ontology ◽  
Regulatory T Cells ◽  
Early Rheumatoid Arthritis ◽  
Whole Blood ◽  
Differentially Expressed ◽  
Rna Seq ◽  
Double Blind

Background:Tocilizumab (TCZ) is a monoclonal antibody that binds to the interleukin 6 receptor (IL-6R), inhibiting IL-6R signal transduction to downstream inflammatory mediators. TCZ has shown to be effective as monotherapy in early rheumatoid arthritis (RA) patients (1). However, approximately one third of patients inadequately respond to therapy and the biological mechanisms underlying lack of efficacy for TCZ remain elusive (1). Here we report gene expression differences, in both whole blood and peripheral blood mononuclear cells (PBMC) RNA samples between early RA patients, categorized by clinical TCZ response (reaching DAS28 < 3.2 at 6 months). These findings could lead to identification of predictive biomarkers for TCZ response and improve RA treatment strategies.Objectives:To identify potential baseline gene expression markers for TCZ response in early RA patients using an RNA-sequencing approach.Methods:Two cohorts of RA patients were included and blood was collected at baseline, before initiating TCZ treatment (8 mg/kg every 4 weeks, intravenously). DAS28-ESR scores were calculated at baseline and clinical response to TCZ was defined as DAS28 < 3.2 at 6 months of treatment. In the first cohort (n=21 patients, previously treated with DMARDs), RNA-sequencing (RNA-seq) was performed on baseline whole blood PAXgene RNA (Illumina TruSeq mRNA Stranded) and differential gene expression (DGE) profiles were measured between responders (n=14) and non-responders (n=7). For external replication, in a second cohort (n=95 therapy-naïve patients receiving TCZ monotherapy), RNA-seq was conducted on baseline PBMC RNA (SMARTer Stranded Total RNA-Seq Kit, Takara Bio) from the 2-year, multicenter, double-blind, placebo-controlled, randomized U-Act-Early trial (ClinicalTrials.gov identifier: NCT01034137) and DGE was analyzed between 84 responders and 11 non-responders.Results:Whole blood DGE analysis showed two significantly higher expressed genes in TCZ non-responders (False Discovery Rate, FDR < 0.05): urotensin 2 (UTS2) and caveolin-1 (CAV1). Subsequent analysis of U-Act-Early PBMC DGE showed nine differentially expressed genes (FDR < 0.05) of which expression in clinical TCZ non-responders was significantly higher for eight genes (MTCOP12, ZNF774, UTS2, SLC4A1, FECH, IFIT1B, AHSP, and SPTB) and significantly lower for one gene (TND2P28M). Both analyses were corrected for baseline DAS28-ESR, age and gender. Expression of UTS2, with a proposed function in regulatory T-cells (2), was significantly higher in TCZ non-responders in both cohorts. Furthermore, gene ontology enrichment analysis revealed no distinct gene ontology or IL-6 related pathway(s) that were significantly different between TCZ-responders and non-responders.Conclusion:Several genes are differentially expressed at baseline between responders and non-responders to TCZ therapy at 6 months. Most notably, UTS2 expression is significantly higher in TCZ non-responders in both whole blood as well as PBMC cohorts. UTS2 could be a promising target for further analyses as a potential predictive biomarker for TCZ response in RA patients in combination with clinical parameters (3).References:[1]Bijlsma JWJ, Welsing PMJ, Woodworth TG, et al. Early rheumatoid arthritis treated with tocilizumab, methotrexate, or their combination (U-Act-Early): a multicentre, randomised, double-blind, double-dummy, strategy trial. Lancet. 2016;388(10042):343-55.[2]Bhairavabhotla R, Kim YC, Glass DD, et al. Transcriptome profiling of human FoxP3+ regulatory T cells. Human Immunology. 2016;77(2):201-13.[3]Gosselt HR, Verhoeven MMA, Bulatovic-Calasan M, et al. Complex machine-learning algorithms and multivariable logistic regression on par in the prediction of insufficient clinical response to methotrexate in rheumatoid arthritis. Journal of Personalized Medicine. 2021;11(1).Disclosure of Interests:None declared

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