tbuckley/cabot-search huggingface dataset:
DNA methylation dynamics during early plant life
Authors: Daniel Bouyer, Amira Kramdi, Mohamed Kassam, Maren Heese, Arp Schnittger, François Roudier, Vincent Colot
Journal: Genome biology (2017)

Cytosine methylation is crucial for gene regulation and silencing of transposable elements in mammals and plants. While this epigenetic mark is extensively reprogrammed in the germline and early embryos of mammals, the extent to which DNA methylation is reset between generations in plants remains largely unknown. Using Arabidopsis as a model, we uncovered distinct DNA methylation dynamics over transposable element sequences during the early stages of plant development. Specifically, transposable elements and their relics show invariably high methylation at CG sites but increasing methylation at CHG and CHH sites. This non-CG methylation culminates in mature embryos, where it reaches saturation for a large fraction of methylated CHH sites, compared to the typical 10-20% methylation level observed in seedlings or adult plants. Moreover, the increase in CHH methylation during embryogenesis matches the hypomethylated state in the early endosperm. Finally, we show that interfering with the embryo-to-seedling transition results in the persistence of high CHH methylation levels after germination, specifically over sequences that are targeted by the RNA-directed DNA methylation (RdDM) machinery. Our findings indicate the absence of extensive resetting of DNA methylation patterns during early plant life and point instead to an important role of RdDM in reinforcing DNA methylation of transposable element sequences in every cell of the mature embryo. Furthermore, we provide evidence that this elevated RdDM activity is a specific property of embryogenesis.
Genetic Alterations Predict Outcomes in Patients with Myelodysplastic Syndrome Receiving Allogeneic Hematopoietic Stem Cell Transplantation
Authors: R. Coleman Lindsley, Wael Saber, Brenton G. Mar, Robert A Redd, Michael D Haagenson, Peter V Grauman, Stephen R. Spellman, Stephanie J. Lee, Tao Wang, Michael R. Verneris, Katharine C. Hsu, Katharina Fleischhauer, Corey S. Cutler, Joseph H. Antin, Donna S. Neuberg, Benjamin L. Ebert
Journal: Blood (2016)
THU0230 HIF1A (RS11549465) and AKNA (RS10817595) gene polymorphisms are associated with primary sjÖgren's syndrome
Authors: G Hernandez-Molina, JM Rodríguez-Pérez, J Fernández-Torres, G Lima, N Pérez-Hernández, A Lόpez-Reyes, GA Martínez-Nava
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> HIF-1α is the main transcriptional regulator of cellular and developmental response to hypoxia, and also participates in the integration of the T cell receptor and cytokine receptor-mediated signals of CD4+ helper cells. Another transcription factor also involved in the immune responses is the AT-hook transcription factor (AKNA). <h3>Objectives</h3> To evaluate the allele and genotype frequencies of polymorphic sites of <i>HIF1A</i> and <i>ANKA</i> genes in primary Sjögren9s syndrome (pSS). <h3>Methods</h3> We included 110 patients with pSS and 141 ethnically matched healthy controls. Three <i>HIF1A</i> gene polymorphisms <i>(Pro582Ser, Ala588Thr, and C191T) and two AKNA genes polymorphism (-1372C</i>&gt;<i>A, and Pro624Leu</i>) were genotyped using TaqMan probes in a Real-Time PCR instrument. Associations between pSS and genotypes, alleles and inheritance models of the SNPs of interest were evaluated by logistic regression adjusted by age and gender. <h3>Results</h3> Most of the patients were females (95.4%), median age 55 years and median disease duration of 7.8 years. The <i>C/T</i> genotype and the <i>T</i> allele of the <i>HIF1A</i><i>Pro582Ser</i> polymorphism protected against pSS (OR=0.22; 95% CI=0.09–0.52; <i>P</i>&lt;0.01; and OR=0.26; 95% CI=0.12–0.58; <i>P</i>&lt;0.01; respectively). Whereas under a recessive model adjusted by age and gender, the <i>AKNA -1372C</i>&gt;<i>A</i> polymorphism A/A genotype was associated with an increased risk of pSS (OR=2.60; 95% CI=1.11–6.12; <i>P</i>=0.03). Parotid enlargement was associated with the <i>HIF1A</i> gene polymorphism (rs11549465), conferring protection for the C/T genotype vs. C/C (OR=0.22; 95% CI 0.05–0.90, <i>P</i>=0.03). The allele T of the same polymorphism was also associated with parotid enlargement (OR=0.24, 95% CI=0.65–0.95; <i>P</i>=0.04). We did not find any association with any other clinical or serological feature. <h3>Conclusions</h3> We identified <i>HIF1A</i><i>Pro582Ser T</i> allele and <i>C/T</i> genotype as well as <i>AKNA -1372C</i>&gt;<i>A</i> polymorphism A/A genotype as genetic factors associated with pSS. Further studies in other populations are needed to validate our findings and to shed some light on their functional implications. <h3>References</h3> Palazon A, Goldrath A, Nizet V, Johnson R. HIF transcription factors, inflammation and immunity. Immunity 2014; 41:518–28. Sims-Mourtada JC, Bruce S, McKeller MR, et al. The human AKNA gene expresses multiple transcripts and protein isoforms as a result of alternative promoter usage, splicing, and polyadenylation. DNA Cell Biol 2005;24:325–38. <h3>Disclosure of Interest</h3> None declared
SAT0650 [18F]FLUORO-PEG-FOLATE pet: a novel imaging technique to visualize rheumatoid arthritis
Authors: N Verweij, S Bruijnen, Y Gent, M Huisman, G Jansen, C Molthoff, Q Chen, P Low, A Windhorst, A Lammertsma, O Hoekstra, A Voskuyl, C van der Laken
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Imaging arthritis activity in rheumatoid arthritis (RA) patients using PET macrophage tracers holds promise for both early diagnostics and monitoring response to therapy (1,2). Previously, (<i>R</i>)-[<sup>11</sup>C]PK11195 has been used, but this macrophage tracer is limited due to high background uptake, especially in bone and bone marrow. Recently, a novel macrophage tracer, [<sup>18</sup>F]fluoro-PEG-folate, was developed, which showed excellent targeting of the folate receptor beta on activated macrophages in synovial tissue in a preclinical arthritic rat model (3). <h3>Objectives</h3> To assess the value of [<sup>18</sup>F]fluoro-PEG-folate PET-CT for imaging inflamed joints in patients with clinically active RA. <h3>Methods</h3> Nine RA patients with at least two clinically inflamed hand joints were included. PET-CT scans of the hands were acquired after intravenous administration of either 185 MBq of [<sup>18</sup>F]fluoro-PEG-folate (n=6) or 425 MBq of (<i>R</i>)-[<sup>11</sup>C]PK11195 (n=3). Volumes of Interest (VOI) were drawn over joints with visually marked uptake and Standardized Uptake Values (SUVs) were calculated. Background VOIs were drawn on metacarpal bone in order to calculate Target-to-Background (T/B) ratios. <h3>Results</h3> No side effects were observed, establishing the safety of [<sup>18</sup>F]fluoro-PEG-folate for use in humans. [<sup>18</sup>F]fluoro-PEG-folate clearly showed uptake in arthritic joints, as shown in Figure 1. In patients scanned with [<sup>18</sup>F]fluoro-PEG-folate, 25 positive joints were seen, with a minimum of two joints per patient. Clinical arthritis was confirmed in 10 of these 25 joints, and was absent in 15 positive joints, suggesting the presence of subclinical inflammation. Whilst both [<sup>18</sup>F]fluoro-PEG-folate and (<i>R</i>)-[<sup>11</sup>C]PK11195 accumulated in arthritic joints, [<sup>18</sup>F]fluoro-PEG-folate showed a significantly lower background uptake than (<i>R</i>)-[<sup>11</sup>C]PK11195 (SUV of 0.18 vs 0.75; p&lt;0.001) respectively. T/B-ratios were significantly higher for [<sup>18</sup>F]fluoro-PEG-folate (3.60vs 1.72, p=0.009). <h3>Conclusions</h3> This first in patient study clearly demonstrates the potential of [<sup>18</sup>F]fluoro-PEG-folate PET-CT as macrophage tracer to image both clinically and sub-clinically affected joints in RA patients. [<sup>18</sup>F]fluoro-PEG-folate showed better characteristics for arthritis imaging than the established tracer (<i>R</i>)-[<sup>11</sup>C]PK11195 because of its lower background signal. <h3>References</h3> Gent YY, et al. J Rheumatology. 2014; 41: 2145–52. Gent YY, et al. Arthritis Rheum. 2012; 64: 62–6. Gent YY, et al. Arthritis Res Ther. 2013; 15: R37. <h3>Disclosure of Interest</h3> None declared
AB0636 A comparison study of prevalence of traditional cardiovascular risk factors and framingham risk score in systemic sclerosis patients and matched controls
Authors: J Sousa-Neves, M Cerqueira, D Santos-Faria, J Leite Silva, C Afonso, F Teixeira
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> In Systemic Sclerosis (SSc), data on prevalence of traditional cardiovascular (CV) disease risk factors is scarce and conflicting (1). Therefore, SSc patients CV risk attributed to traditional CV risk factors remains an issue of debate. <h3>Objectives</h3> To evaluate if patients with SSc have a higher prevalence of traditional CV disease risk factors and a higher risk of long-term CV events based on the risk prediction tool of the Framingham risk score (FRS) in comparison with age, race and sex matched control subjects. <h3>Methods</h3> The study comprised patients diagnosed with SSc, fulfilling both the 1980 ACR and the 2013 ACR/EULAR criteria for the disease, and followed-up at our Rheumatology Department and a group of age, race and sex-matched controls. Inclusion criteria were age 30 to 74 and no history of CV events in order to calculate FRS. In total, 46 out of 62 patients were eligible for the study. Traditional CV disease risk factors (diabetes, arterial hypertension and smoking) were compared among the 46 patients with SSc and 51 matched controls. Systolic blood pressure (SBP) values and total and high-density lipoprotein (HDL) cholesterol levels were also collected. The 10-year risk for CV events according to FRS was calculated and means of patients and controls were compared. Subjects9 distribution into 3 categories of risk – low (&lt;10% risk), medium (10–20% risk) and high (&gt;20% risk) was also compared. Parametric and nonparametric tests were used for comparison between groups. P value &lt;0.05 was defined as statistically significant. <h3>Results</h3> Mean risk for CV events in 10-years assessed by FRS was 10.00%±8.61 for SSc patients and 7.76%±8.30 for matched controls. Differences were not statistically significant (p=0.196). Additionally, prevalence of diabetes, arterial hypertension and smoking did not differ significantly between the two groups (p=0.890, p=0.443, p=0.651, respectively). Total and HDL cholesterol levels were also similar between groups (p=0.963 and p=0.506, respectively). Only SBP values (mmHg) of SSc patients were significantly higher (128.50 mmHg [113.5 to 139.3]) (median [interquartile range]) compared with controls (120.00 [110 to 130]), p=0.031. Subjects9 distribution into the 3 groups of risk defined was similar for both groups (p=0.205). <h3>Conclusions</h3> In our study, prevalence of traditional CV disease risk factors and 10-year risk for CV events based on FRS assessment tool did not differ significantly between SSc patients and age, sex and race matched controls. <h3>References</h3> Psarras A, Soulaidopoulos S, Garyfallos A, Kitas G and Dimitroulas T. A critical view on cardiovascular risk in systemic sclerosis. Rheumatol Int. 2017 Jan;37(1):85–95. <h3>Disclosure of Interest</h3> None declared
Capsule switching of Neisseria meningitidis sequence type 7 serogroup A to serogroup X
Authors: Xuemeng Ji, Ping-Ping Yao, Le-Yi Zhang, Yi Li, Fang Xu, Ling-Ling Mei, Shui-Rong Zhu, Yan-Jun Zhang, Han-Ping Zhu, Stijn van der Veen
Journal: Journal of Infection (2017)
AB0434 Tofacitinib in rheumatoid arthritis: real life experience
Authors: P Sansinanea, AC Costi, A Vulcano, AP Salas, J Marcos, MA Belini, MA García
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Tofacitinib is a new small molecule, Janus kinase 1 and 3 inhibitor, interfering with the JAK-STAT signaling pathway. The JAK-STAT transmits the extracellular information in the cell nucleus, influencing DNA transcription. Its efficacy and safety in Rheumatoid Arthritis (RA) has been demonstrated in different phase II, III and long-term clinical studies. It has been approved in Argentina for the treatment of patients with moderate to severe rheumatoid arthritis RA with failure to conventional DMARDs. <h3>Objectives</h3> To communicate real world safety data from patients with RA under treatment with Tofacitinib. <h3>Methods</h3> A retrospective, descriptive study from patients with RA (ACR/EULAR2010) under treatment with Tofacitinib from September 2014 to December 2016 was conducted. Medical records from patients being treated with Tofacitinib were reviewed and demographic data were recorded. Comorbidities, concomitant treatments, and reported adverse effects were documented. <h3>Results</h3> 62 patients were treated with Tofacitinib. 53 were female and 9 were male, with a mean age of 57.91±14.72 years and average disease duration of 140.09±130.83 months. 18 patients (29%) had at least one comorbidity, the most frequent being hypertension (77%). Of the 62 patients studied, 54 (87%) had established RA (duration of illness greater than 24 months) and 8 patients (13%) with early RA (less than 24 months). In 54 patients Tofacitinib was indicated in combination with another DMARD (87%), and only 6 patients received treatment as monotherapy. The most commonly used DMARD in combination therapy was methotrexate (MTX) in 92.5% Treatments were indicated by failure to MTX or other conventional DMARDs, 12/62 treatments were indicated by failure to treatment with 1 biological DMARD and 13/62 treatments were indicated by failure to two or more biological DMARDs. The maximum exposure time was 21 months. During the time of exposure to Tofacitinib the following adverse events were observed: Herpes Zoster infection 2 cases (monometameric, no visceral involvement in unvaccinated patients), upper airway infection 1 case, transient increase in liver enzymes 1 case, peripheral facial paralysis 1 case, tachycardia 1 case. There were no cases of serious infections, opportunistic infections, cytopenias, dyslipidemia, or increased CPK. Three patients discontinued Tofacitinib: one due to tachycardia, another case peripheral facial paralysis and another case due inefficacy. <h3>Conclusions</h3> Most patients received combined treatment with DMARDs being the most commonly used Methotrexate. There were no cases of serious infections, opportunistic infections, cytopenias or dyslipidemia. The use of Tofacitinib in RA patients in our cohort showed a comparable safety profile with long-term extension studies in the treatment of patients with RA diagnosed with failure of conventional or biological DMARDs. <h3>Disclosure of Interest</h3> None declared
SP0065 Are we asking the right questions in transition research?
Authors: K Minden
Journal: Annals of the Rheumatic Diseases (2017)

Already in 1991 Robert Blum pointed to the diverse set of issues of which the clinicians need to be cognisant to successfully care for youth with chronic illness. Since then, the special health care needs of adolescents and young adults with chronic diseases, including rheumatic diseases, have been on the agenda. Despite efforts to develop holistic services and programmes for youth, there are still inconsistencies in service delivery and practice standards. This revealed a survey among paediatric rheumatologists from 115 centres in 22 European countries in 2016. A minority of European paediatric rheumatology centres have a written transition policy, follow a standardised, structured approach in transitioning patients and measure the success of their interventions with evaluated instruments. To overcome these deficits and existing practice variation, key elements of transitional care, frameworks and pathways to implement and assess transition programmes have been recommended by EULAR and PRES. However, as long as we don9t have robust evidence upon best practice for transition, on the best metrics for measuring “success” and “outcome” of transitional care services and on the impact of interventions on the young people with rheumatic diseases will the service planning and delivery for transition aged youth remain suboptimal and result in adverse long-term outcomes. The literature about transitional care is exponentially increasing each year and comprises among others assessments of experience of care and clinical outcomes, evaluations of different services and processes of care. What we have learned so far from transition research in the field of rheumatology, which research priorities are currently set on the agenda by health care providers and whether they meet those of young people will be in the focus of this lecture. <h3>Disclosure of Interest</h3> None declared
Single-Cell Analysis of Clonal Dynamics in Childhood ALL Reveals a Key Role for Transcriptional Intratumor Heterogeneity in Driving Resistance to Chemotherapy
Authors: Virginia A Turati, José Afonso Guerra-Assunção, John C Ambrose, John Brown, Mike Hubank, Alex Hobbs, Mark Lynch, Bernadett Gaal, Sarah Inglott, Lucia Conde, Simon Richardson, Javier Herrero, Sten Eirik Jacobsen, Tariq Enver
Journal: Blood (2016)
The establishment and validation of novel therapeutic targets to retard progression of chronic kidney disease
Authors: Carol Pollock, Anna Zuk, Hans-Joachim Anders, Mohammad Reza Ganji, David W. Johnson, Bertram Kasiske, Robyn G. Langham, Roberto Pecoits-Filho, Giuseppe Remuzzi, Jerome Rossert, Yusuke Suzuki, Tetsuhiro Tanaka, Robert Walker, Chih-Wei Yang, Joseph V. Bonventre
Journal: Kidney International Supplements (2017)
FRI0395 Incidence of myositis-specific autoantibody (MSA) specificities in sera referred to new zealand (NZ) medical laboratories
Authors: J O'donnell, P Keating, M van Voorthuizen, J Liu, I Chua, A Soepnel, E Gumbley, M Spellerberg
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Idiopathic inflammatory myopathies can be classified by clinicopathological phenotype into four major groups: overlap myositis (OM), dermatomyositis (DM), immune mediated necrotising myositis (IMMNM) and inclusion body myositis (IBM). The different phenotypes associate with distinct MSA specificities although a variable percentage within each group are seronegative and the majority of IBM patients are seronegative<sup>1</sup>. No commercial assay for the IBM associated specificity, cN1A, is available. In NZ testing for MSA is restricted to two laboratories: Waikato Hospital (WHL) and Canterbury Health Laboratories (CHL). Both laboratories use the commercial Euroimmun Euroline assay. In addition CHL has developed an ELISA for anti HMGCR autoantibodies and receives referrals from throughout NZ. <h3>Objectives</h3> To define the incidence and specificities of MSA in serum samples referred for testing in New Zealand. <h3>Methods</h3> For the period 3 November 2015 to 2 November 2016 each laboratory information system (LIS) was interrogated for requests for MSA. For the purposes of this report positive results were grouped into the specificities associated with each of the defined clinicopathological phenotypes. DM: Mi2, Tif-γ, MDA 5 NXP2 SAE1 OM: Ku, PM-Scl-100, PL75, Jo1, PL-7, PL-12, EJ, OJ IMMNM: HMGCR, SRP <h3>Results</h3> Of screened sera (n=793, CHL=622, WHL=171) 11% were positive for MSA (88/793). Positive sera where distributed amongst three clinicopathological associated autoantibody specificities: DM 23% OM 50%,IMMNM 27%. The most common serum specificities were HMGCR (n=24) and Jo-1 (n=13). No serum with specificities to SRP or OJ was detected. 22/24 sera positive for anti HMGCR had an elevated CPK concentration (CPK&gt;2500u/l in 21/24 and CPK=544 in 1/24, reference range =66–220). <h3>Conclusions</h3> In New Zealand 11% of sera referred for MSA testing were positive. As a group the most common specificities were those associated with OM while the most common antigen specificity was to HMGCR. Anti-HMGCR antibodies were almost invariably associated with major elevations in serum CPK. <h3>References</h3> Beveniste O, Stenzel W, Allenbach Y. Advances in serological diagnostics of inflammatory myopathies. Curr Opin Neurol 2016;29:662–673. <h3>Disclosure of Interest</h3> None declared
THU0533 Do jia core outcome variables at baseline predict clinically inactive disease states at one year?
Authors: SJW Shoop-Worrall, SM Verstappen, JE McDonagh, W Thomson, KL Hyrich
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Identifying predictors for early clinically inactive disease (CID) would allow stratified treatment decisions at diagnosis, minimising the burden of unnecessary therapies. JIA core outcome variables (COVs) are routinely collected and would therefore be convenient predictors. However, different groups of children are identified by current CID definitions (Wallace9s preliminary criteria vs. clinical Juvenile Arthritis Disease Activity Score in 10 joints (cJADAS10)) and predictors may differ depending on which CID outcome is applied. <h3>Objectives</h3> To assess whether baseline COVs predict achievement of CID according to Wallace9s preliminary criteria or the cJADAS10 cut-off in patients with JIA. <h3>Methods</h3> Children and young people enrolled to the Childhood Arthritis Prospective Study (CAPS), a UK multicentre inception cohort, before January 2011, were selected if diagnosed with oligoarticular, RF-negative or RF-positive polyarticular JIA. At one year following initial presentation to paediatric rheumatology, children were classified as i) CID according to Wallace9s preliminary criteria and ii) CID according to cJADAS10. Baseline COVs (active joint count, limited joint count, physician9s global, parental global, functional ability (Childhood Health Assessment Questionnaire (CHAQ)) and ESR) were tested for predictive ability for these outcomes using univariate and forced-entry multivariate logistic regressions, adjusting for age and symptom duration at initial presentation, gender and ILAR subtype. Multiple imputation accounted for missing data. <h3>Results</h3> Of 829 children included, 70% were female and the majority had oligoarticular JIA (68%). At one year, 28% had achieved CID according to Wallace9s preliminary criteria and 38% according to the cJADAS10 (21% CID on both). In univariate analyses, increased baseline CHAQ and physician9s global assessment score predicted lower odds of achieving both CID states. In addition, increased active joints (OR: 0.97, 95% CI0.94, 0.99), and patient/parent global assessment scores (OR: 0.87, 95% CI 0.81, 0.93) predicted lower odds of CID on the cJADAS10 only. In multivariate analyses, one increased CHAQ point at baseline independently predicted 28% lower odds of CID on the cJADAS10 (95% CI 0.53, 0.98). However, no baseline COVs predicted CID on Wallace9s preliminary criteria. No demographic variables were significantly predictive in any model. <h3>Conclusions</h3> There were different predictors for CID on the cJADAS10 vs. Wallace9s preliminary criteria. Children with poor functional ability at initial presentation are less likely to achieve CID on the cJADAS10. These children could be targeted with more aggressive treatment strategies to better control their disease. <h3>Disclosure of Interest</h3> None declared