tbuckley/cabot-search huggingface dataset:
Something Old, Something New: The Tumor Microenvironment Comes of Age
Authors: Kerrie L. Marie, Glenn Merlino
Journal: Cancer Discovery (2019)

In this issue, Weeraratna and colleagues demonstrate that observed differences in melanoma aggressiveness in younger versus older patients can be explained not just by cell-intrinsic alterations over time, but by age-dependent changes in fibroblasts and the extracellular matrix they help create. Their findings identify novel cellular targets for melanoma therapy, as well as candidate prognostic biomarkers to better inform clinical decisions for patients with melanoma.See related article by Kaur et al., p. 64.See related article by Ecker et al., p. 82.
OP0282 New systemic sclerosis risk loci identified through a meta-gwas strategy
Authors: E. López-Isac, M. Acosta-Herrera, S. Assassi, C.P. Simeón, P.E. Carreira, I. Castellví, N. Ortego-Centeno, L. Beretta, C. Lunardi, A. Gabrielli, G. Moroncini, N. Hunzelmann, T. Witte, J.H. Distler, A. Franke, A.E. Voskuyl, J. de Vries-Bouwstra, C. Wijmenga, R. Hesselstrand, A. Nordin, A.-M. Hoffmann-Vold, A. Herrick, J. Worthington, C.P. Denton, M.A. Brown, Y. Allanore, T.R. Radstake, C. Fonseca, M.D. Mayes, J. Martín
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> In systemic sclerosis (SSc), previous GWASs have identified several <i>loci</i> associated with the disease, but their rate of discovery has been limited due to modest sample sizes. Extensive collaborative efforts have enabled us to gather the largest cohort of SSc patients. In the present study, we have performed a large meta-GWAS taking advantage of our well-powered cohort. <h3>Objectives</h3> To continue unravelling the complex genetic component of SSc. <h3>Methods</h3> The complete set of individuals enrolled for this study comprised a total of 26 679 genome-wide genotyped individuals of European ancestry. PLINK and EIGENSTRAT were used for quality control and population stratification adjustments. Genotype imputation was performed with IMPUTE2 and the 1000 Genome Project Phase 3 as reference panel. <h3>Results</h3> Twenty-three <i>loci</i> reached the genome-wide significance level (<i>p</i>-value&lt;5×10–8) in our large-scale meta-analysis. Twelve out of the total significant signals represented new associations and involved novel pathways in the pathophysiology of the disease. Significant enrichment was observed for epigenetic marks of active promoters and active enhancers in critical cell types for the disease. In addition many of the interrogated variants correlated with eQTLs thus altering gene expression. <h3>Conclusions</h3> Using a large meta-GWAS, we have identified twelve novel associations for SSc susceptibility and confirmed several previously reported risk <i>loci</i>. These results considerably increase our understanding of the genetic basis of SSc and shed light on the pathogenesis of the disease providing important information to discover new therapeutic targets genetically validated. <h3>Disclosure of Interest</h3> None declared
Wildfires Disaster Guidance: Tips for Staying Healthy during Wildfires
Authors: Shazia Jamil, W. Graham Carlos, Lorriana Leard, Angela Wang, Lekshmi Santhosh, John Balmes, Nitin Seam, Charles S. Dela Cruz
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

"Wildfires Disaster Guidance: Tips for Staying Healthy during Wildfires." American Journal of Respiratory and Critical Care Medicine, 199(2), pp. P3–P4
PARE0002 Adherence to therapy and patients engagement in italy: a close link
Authors: U.G. Viora, R. Broggini, G. Campolieti, F. Leonardi, F. Padovani, S. Tonolo
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> In the last years ANMAR Italia and the federated Regiional Association worked hardly to educate people with Rheumatic diseases (RMDs) to an appropriate adherence to the therapy prescribed, as the Mosaico project confirmed that even patients in bio-technological therapies reveal unwillingness to assume their drugs within the schedule prescribed by the rheumatologist (timing and doses). “ANMAR we care”, study by the Italian Association of patients with Rheumatic diseases (ANMAR) in 2017 thnaks to an unrestricted grant from ABBVIE and the precious collaboration of the Engage Minds Hub Research Center of Università Cattolica del Sacro Cuore di Milano directed by prof. Guendalina Graffigna, intended to analize the problem again after the campains acted in the last two years and to link adherence to theapies with the degree of patient engagement. <h3>Objectives</h3> to verify the percentage of adherent patients and their degree of adhesion to the therapy. To appraise the relationship among adherence and engagement of people with rheumatic diseases. <h3>Methods</h3> in the study we administered to patients a specifically pursued questionnaire containing a fair number of questions on adherence to therapies. This sub-analysis was made using the answers to those questions and data have been interpolated with those related to the level of engagement of the patients. <h3>Results</h3> overall data confirm that in Italy also in 2017 the percentage of people with RMDs adherent to therapies settles in dissatisfying degrees (54%) and that such includes patients partially adherent. Looking at the relationship within adherence and engagement, if divided in the four groups anticipated by the PHE Model the percentage are: Blackout (cognitive blindness, deny, freezing) 47%, Arousal (superficial knowledge, alert, behavioral disorganization) 46%, Adhesion (cognitive adhesion, accep-tance, formal adherence) 61%, Eudaimonic Project (sense making, elaboration, situated practices) 78%. Notice that patients with Psoriatic Arthritis are the most adherent, followed by those with Fibromialgy, Spondylitis and finally with Rheumatoid Arthritis. <h3>Conclusions</h3> this analysis highlights that the information and awareness campaigns made in the last years were useful, but results are still far away from the optimum. As we expected, the engagement degree hardly affects the adherence process, but totally unexpected is that patients in “Arousal” are more confused and less adherent than those in “Blackout”. <h3>Disclosure of Interest</h3> None declared
Abstract 13816: Dantrolene Enhances Binding of Calmodulin to RyR2 in CPVT Which Mutation Located at Central Domain but Does Not Enhance That in CPVT With Mutation at CaM-like Domain
Authors: Shigehiko Nishimura, Takeshi Yamamoto, Go Fukui, Takako Maeda, Akihiro Hino, Takeshi Suetomi, Makoto Ono, Mamoru Mochizuki, Tetsuro Oda, Shinichi Okuda, Shigeki Kobayashi, Masafumi Yano
Journal: Circulation (2015)

Introduction: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by heterozygous mutation in RyR2 gene. Most mutations are known to be located at N-terminal domain, central domain or C-terminal channel pore region. Meanwhile, amino acid residues from 4026 to 4172 of RyR2 have EF hand motifs and are called calmodulin (CaM)-like domain (CaMLD). Some of the human CPVT mutations were reported in this CaMLD. In this study we investigated the molecular mechanism of arrhythmogenesis of CPVT with mutation at CaMLD comparing R2474S and N4103K KI mice. Methods and Results: VT and/or Vf were frequently observed after caffeine plus epinephrine infusion in KI mice (R2474S: 100%, N4103K: 43%), but not in WT mice. CaM binding affinity to RyR2 was assessed by incorporation of exogenous CaM labeled with HiLyte Fluor® in isolated saponin-permeabilized cardiomyocytes. The CaM binding affinity was decreased in both R2474S-KI (Kd: 400 nM) and N4103K-KI cells (Kd: 165 nM) compared with WT cells (Kd: 90 nM) in the presence of cAMP. Addition of 1 μM dantrolene (DAN), the zipper of N-terminal and central domain of RyR2, increased the affinity of CaM to RyR2 in R2474S-KI cells, but did not increase that in N4103K-KI cells. Frequency of the Ca 2+ sparks (SpF) was measured in isolated saponin-permeabilized cardiomyocytes. SpF was much higher in KI cells than in WT cells (R2474S-KI: 17.2±6.7, N4103K-KI: 21.5±6.3, WT: 10.6±4.1). Addition of 1 μM DAN to R2474S-KI cells significantly decreases SpF (10.4±5.5), however, DAN did not decrease SpF in N4103K-KI (21.8±6.9). Spontaneous Ca 2+ transient (SCaT) was measured during sequential pacing from 1 to 5 Hz in isolated intact cardiomyocytes. The SCaT was rarely observed in WT cells even with 10 nM isoproterenol, whereas that was observed in 37 % of R2474S-KI and in 33 % of N4103K-KI cells. Addition of DAN to KI cells, decrease frequency of SCaT in R2474S-KI (13 %), however, did not decrease in N4103-KI cells (30 %). Conclusions: In CPVT with central domain mutation, domain zipper is effective to inhibit arrhythmias. In CaMLD mutation, structural abnormality might be in the downstream of the N-terminal and central domain switch, so that the DAN is not effective. CaMLD might be a novel therapeutic target of lethal arrhythmias.
OP0351 First diagnosis of uveitis is not higher among juvenile idiopathic arthritis (JIA) patients receiving etanercept compared to methotrexate
Authors: R. Davies, D. De Cock, L. Kearsley-Fleet, A. Ramanan, K.L. Hyrich
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Uveitis is a common comorbidity among patients with juvenile idiopathic arthritis (JIA), occurring in approximately 1 in 10 JIA patients. Among other risk factors such as early ageat JIA onset, shorter disease duration and oligoarticular subtype, the use of etanercept (ETN) may also increase the risk of developing uveitis. However, previous studies have produced conflicting results, often limited by small sample sizes and limited follow-up time. <h3>Objectives</h3> To determine if patients receiving ETN have a higher risk of developing uveitis for the first time compared to patients receiving methotrexate (MTX). <h3>Methods</h3> The study population comprised JIA subjects recruited to the BSPAR ETN Cohort Study at point of starting ETN or MTX. Only patients with no prior history of uveitis were included. This was an on-drug analysis, whereby events were only included if the patient was on ETN or MTX at the time of uveitis onset. Follow-up began from date of first treatment to first uveitis diagnosis, discontinuation of ETN or MTX, most recent follow-up up to 30/11/16 or death, whichever came first. Crude incidence rates of uveitis per 100 person years (pyears) were calculated. Hazard ratios (HR) comparing risk of uveitis with ETN versus MTX were calculated using propensity adjusted Cox regression. <h3>Results</h3> Of 1517 patients, 1009 were registered to the ETN cohort (all receiving ETN) and 508 to the MTX cohort. ETN patients were older, with longer disease duration, and were less likely to have persistent oligoarthritis. The mean age at uveitis diagnosis was 8 years in the ETN cohort versus 5 years in the MTX cohort. The HR adjusted for age and gender, disease scores, disease duration, baseline steroid use, co-morbidity, ILAR subtype, and ethnicity found a lower risk of developing uveitis inpatients receiving ETN compared to MTX (0.30, 95% CI (0.10–0.90)) (table 1). <h3>Conclusions</h3> Within this cohort of UK children with JIA, a new diagnosis of uveitis is not more common among children receiving ETN compared to MTX, even after taking into account differences inage and disease duration between the cohorts. This is reassuring given there ports of possible increased risk of uveitis among children with JIA receiving ETN. Age appears to be a major influencing factor as patients in the MTX cohort were younger thus at a higher risk of uveitis. For patients with a high eruveitis risk other treatments options could have been selected, leading to possible confounding by indication, which in turn makes ETN look protective. Researchers should take these selection biases into account when analysing their results. <h3>Disclosure of Interest</h3> None declared
Premature polyadenylation-mediated loss of stathmin-2 is a hallmark of TDP-43-dependent neurodegeneration
Authors: Ze’ev Melamed, Jone López-Erauskin, Michael W. Baughn, Ouyang Zhang, Kevin Drenner, Ying Sun, Fernande Freyermuth, Moira A. McMahon, Melinda S. Beccari, Jon W. Artates, Takuya Ohkubo, Maria Rodriguez, Nianwei Lin, Dongmei Wu, C. Frank Bennett, Frank Rigo, Sandrine Da Cruz, John Ravits, Clotilde Lagier-Tourenne, Don W. Cleveland
Journal: Nature Neuroscience (2019)
Discovery and Development of MEDI7247, a Novel Pyrrolobenzodiazepine (PBD)-Based Antibody Drug Conjugate Targeting ASCT2, for Treating Hematological Cancers
Authors: Nabendu Pore, Kevin P Schifferli, Noel R Monks, Ravinder Tammali, Martin Borrok, Elaine Hurt, Matt Flynn, Marlon Rebelatto, Danielle M. Townsley, Mary Jane Hinrichs, Rakesh Dixit, Steven Coats, Ronald Herbst, David Tice
Journal: Blood (2018)
Aspirin Use in Venous Thromboembolism Prophylaxis Following Hip or Knee Arthroplasty: A Network Meta-Analysis of Randomized Controlled Trials
Authors: Tarek Haykal, Babikir Kheiri, Mahmoud Barbarawi, Yazan Zayed, Muhammad Shah Miran, Adam Chahine, Ahmed Abdalla, Khalil Katato, Ghassan Bachuwa, Tarik Hadid, Zyad Kafri
Journal: Blood (2018)
B-CAP (brentuximab vedotin, cyclophosphamide, doxorubicin and predniso(lo)Ne) in Older Patients with Advanced-Stage Hodgkin Lymphoma: Results of a Phase II Intergroup Trial By the German Hodgkin Study Group (GHSG) and the Nordic Lymphoma Group (NLG)
Authors: Boris Boell, Alexander Fosså, Helen Goergen, Peter Kamper, Sirpa Leppa, Daniel Molin, Julia Meissner, Ellen Ritter, Jacob H. Christensen, Martin Hutchings, Michael Fuchs, Andreas Engert, Carsten Kobe, Peter Borchmann
Journal: Blood (2018)
Early Normalization of Serum Free Light Chain (FLC) Assays Correlates with Profound and Prolonged Responses in Newly Diagnosed Multiple Myeloma (MM)
Authors: Mercedes Gironella, Alicia Senín, Karla Vallejo, Pamela Arenas, Priyanka Raheja, Romina Dieli, Manuel Hernández, Francesc Bosch
Journal: Blood (2018)
FRI0279 Decreased sphingosin-1-phosphate receptor 1 (S1P1) expression in endothelial progenitor cells (EPCS) from systemic lupus erythematosus (SLE) patients
Authors: J. Romo-Tena, D. Gómez-Martín, L.P. Blanco, C. Carmona-Rivera, R. Carazo-Vargas, J. Alcocer-Varela, M.J. Kaplan
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> SLE patients display an elevated cardiovascular risk when compared to the general population.<sup>1</sup> Interferon-alpha (IFN-α) appears to drive atherogenesis in SLE at least in part, by promoting abnormal phenotype and function of EPCs.<sup>1</sup> S1P1 is considered crucial for vasculogenesis and has been shown to attenuate IFN-α autoamplification by promoting IFN receptor 1 (IFNAR1) degradation.<sup>2,3</sup> <h3>Objectives</h3> To characterise S1P1 expression in EPCs from SLE patients and its putative association to type I IFNs effects on vasculogenesis. <h3>Methods</h3> SLE subjects that fulfilled SLE ACR classification criteria were recruited. Healthy controls were selected based on age and gender. Disease activity was assessed by SLEDAI-2K index. EPCs were quantified by flow cytometry in PBMC subsets as those cells that coexpress CD133<sup>+</sup>/CD34<sup>+</sup> in the CD3<sup>-</sup>/CD56<sup>-</sup>/CD79b<sup>-</sup> gate.<sup>1</sup> S1P1 expression was quantified in that subset. Control PBMCs were cultured in endothelial cell (EC)-enrichment medium for 2 weeks. Differentiated ECs were characterised by immunofluorescence (IF) as those cells that coexpress UEA-1 lectin and take up acetylated LDL.<sup>1</sup> These cells were stimulated with recombinant IFN-α in the presence or absence of the S1P1 agonist CYM-5442 and the S1P1 antagonist W-146 to assess the effect of this pathway on EC differentiation and type I IFN induced gene expression.3 <h3>Results</h3> SLE and matched healthy controls (n=36/group) were compared. Demographic and clinical characteristics are depicted in table 1. <h3>Conclusions</h3> The S1P1 pathway is involved in the regulation of EPC differentiation by type I IFNs. Defects in S1P1 signalling pathway in lupus EPCs may contribute to the development of endothelial dysfunction in SLE. <h3>References</h3> [1] Denny MF. Interferon-alpha promotes abnormal vasculogenesis in lupus: a potential pathway for premature atherosclerosis. Blood2007;110:2907–2915. [2] Liu Y. Edg-1, the G protein-coupled receptor for sphingosine-1-phosphate, is essential for vascular maturation. J Clin Invest2000;106:951–961. [3] Teijaro JR. S1PR1-mediated IFNAR1 degradation modulates plasmacytoid dendritic cell interferon-alpha autoamplification. Proc Natl Acad Sci USA2016;113:1351–1356. <h3>Acknowledgements</h3> This work was supported by a grant from the Colegio Mexicano de Reumatología to DGM. <h3>Disclosure of Interest</h3> None declared
THU0581 Use of biological therapies in adult patients diagnosed with juvenile idiopathic arthritis: results from biobadaser, the spanish registry of adverse events with biologic therapies
Authors: J.J. Bethencourt Baute, C. Sanchez-Piedra, F. Sanchez-Alonso, D. Ruiz-Montesinos, J. Manero, C. Rodriguez-Lozano, E. Perez-Pampin, A. Ortiz, S. Manrique, M.V. Hernandez, C. Campos, A. Sellas, A. Sifuentes, J. García-González, J.J. Gomez-Reino, F. Díaz-Gonzalez, S. Bustabad-Reyes
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Juvenile idiopathic arthritis (JIA) is the most frequent chronic rheumatic disease in childhood. The early disease recognition and treatment is critical to prevent long-term complications and disability in childhood. During the last decade the arrivals of biologics has dramatically changed the prognosis of these patients. A number of well-designed clinical trials, as well as cohort studies have demonstrated that biologics are an effective option for JIA patients who do not respond or cannot tolerate treatment with synthetic disease modifying drugs (DMARDs). JIA is not confined to childhood, and a 41% had active disease are on medication after 30 years and 28% had a high symptom state. <h3>Objectives</h3> The aim of this work was to study the pattern of use, drug survival and adverse events of biologic therapy in JIA patients during the transition period from the diagnostic to the adulthood. <h3>Methods</h3> Information was obtained from BIOBADASER, a safety multicenter prospective registry. All patients included in the registry diagnosed of JIA between 2000 and 2015 were analysed. Proportions, means and standard deviations (SD) were used to describe population. Incidence rates and 95% confidence intervals were calculated to assess adverse events. Kaplan-Meier analysis was used to compare the drug survival. <h3>Results</h3> 469 patients, 46.1% women were included in this study. Age at diagnosis was 9.4 (SD=5.3) and years of disease evolution 24.1 (SD=14.1). The age at biological treatment initiation was 23.9 years (SD=13.9). The pattern of use of biologics in JIA patients in the paediatric age shows a linear increase from 24% in 2000 to 65% in 2014. Interestingly, the biologic suspension for disease remission was higher in patients who initiated its use under 16 years (25.7%) than in those who began at 16 years or later (7.9%, p&lt;0.0001). Serious adverse events showed a total incidence rate of 41.4 (35.2–48.7) (1000 patients/year) without differences between patients younger or older than 16 years old. However, patients younger than 16 years old showed a significant increment in infeccion and infectation (p&lt;0.001). <h3>Conclusions</h3> The biologic survival and suspension by remission was higher when the biologic therapy started before 16 years old in JIA patients. The incidence rate severe adverse events in the childhood and adulthood in JIA patients treated with biologics was similar, however, a significant increment of infection was observed in patients under 16 years old. <h3>Disclosure of Interest</h3> None declared
Modified Transverse-Vertical Gross Examination: a Better Method for the Detection of Definite Capsular Invasion in Encapsulated Follicular-Patterned Thyroid Neoplasms
Authors: Hye-Seon Oh, Sun Jae Kim, Eyun Song, Yu-Mi Lee, Tae-Yon Sung, Won Gu Kim, Tae Yong Kim, Dong Eun Song
Journal: Endocrine Pathology (2019)

The diagnosis of encapsulated follicular-patterned thyroid carcinoma (EFPTC) is challenging, and the detection of capsular invasion and/or vascular invasion is essential in distinguishing benign lesions from malignant lesions. In this study, we present a modified transverse-vertical gross examination method with additional vertical cuts at the upper and lower ends of thyroid nodules. In addition, we compared the clinicopathological characteristics of patients with EFPTC between conventional and modified methods. The diagnostic rate of follicular thyroid carcinoma and invasive encapsulated follicular variant of papillary thyroid carcinoma was higher with the modified method (p = 0.003 and p = 0.028, respectively). Furthermore, the paraffin block number and the number of capsular invasion per centimeter were significantly higher with the modified method (p < 0.001 and p = 0.007, respectively). However, vascular invasion was not significantly different between the two methods (p = 0.771). The possibility of identifying capsular invasion was around two times higher with the modified method (odds ratio = 1.91, 95% confidence interval = 1.20–3.07, p = 0.007). A total of 38 samples (23%) in the modified transverse-vertical group had capsular and/or vascular invasion in the additional vertical cuts of the upper/lower ends of the tumor. Our modified transverse-vertical gross examination method was more effective than the conventional transverse examination method for the detection of capsular invasion in EFPTC. This modified gross examination method might allow a better differential diagnosis among various encapsulated micro-follicular proliferative lesions.