tbuckley/cabot-search huggingface dataset:
Matrix Screen Identifies Synergistic Combination of PARP Inhibitors and Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibitors in Ewing Sarcoma
Authors: Christine M. Heske, Mindy I. Davis, Joshua T. Baumgart, Kelli Wilson, Michael V. Gormally, Lu Chen, Xiaohu Zhang, Michele Ceribelli, Damien Y. Duveau, Rajarshi Guha, Marc Ferrer, Fernanda I. Arnaldez, Jiuping Ji, Huong-Lan Tran, Yiping Zhang, Arnulfo Mendoza, Lee J. Helman, Craig J. Thomas
Journal: Clinical Cancer Research (2017)

Purpose: Although many cancers are showing remarkable responses to targeted therapies, pediatric sarcomas, including Ewing sarcoma, remain recalcitrant. To broaden the therapeutic landscape, we explored the in vitro response of Ewing sarcoma cell lines against a large collection of investigational and approved drugs to identify candidate combinations.Experimental Design: Drugs displaying activity as single agents were evaluated in combinatorial (matrix) format to identify highly active, synergistic drug combinations, and combinations were subsequently validated in multiple cell lines using various agents from each class. Comprehensive metabolomic and proteomic profiling was performed to better understand the mechanism underlying the synergy. Xenograft experiments were performed to determine efficacy and in vivo mechanism.Results: Several promising candidates emerged, including the combination of small-molecule PARP and nicotinamide phosphoribosyltransferase (NAMPT) inhibitors, a rational combination as NAMPTis block the rate-limiting enzyme in the production of nicotinamide adenine dinucleotide (NAD+), a necessary substrate of PARP. Mechanistic drivers of the synergistic cell killing phenotype of these combined drugs included depletion of NMN and NAD+, diminished PAR activity, increased DNA damage, and apoptosis. Combination PARPis and NAMPTis in vivo resulted in tumor regression, delayed disease progression, and increased survival.Conclusions: These studies highlight the potential of these drugs as a possible therapeutic option in treating patients with Ewing sarcoma. Clin Cancer Res; 23(23); 7301-11. ©2017 AACR.
SAT0073 MIR-186-5P targeting IL-33 gene as biomarker to predict subclinical atherosclerosis in patients with early rheumatoid arthritis
Authors: TH Cheng, Q Shang, WY Mak, M Li, KY Kwok, ICW Yim, EKM Li, PCH Wong, VWN Lao, HT Pang, LS Tam
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Patients with rheumatoid arthritis (RA) die prematurely compared with the general population, primarily because of cardiovascular diseases (CVD). Interleukin-33 (IL-33) is a member of the IL-1 cytokine family which was important in the pathogenesis of RA and development of CVD. Blood IL-33 protein was not detectable in most subjects, even in RA patients. Thus, the usability of IL-33 as a biomarker for CVD is limited. MicroRNAs (miRNAs) are small non-coding RNAs that function as post-transcriptional regulators of gene expression. <h3>Objectives</h3> This study was to ascertain if dysregulated miRNAs targeting <i>IL-33</i> gene in early RA (ERA) patients were associated with subclinical atherosclerosis in ERA patients. <h3>Methods</h3> 76 ERA patients were recruited in this cross-sessional study. Potential miRNAs binding to 39UTR of the <i>IL-33</i> gene were predicted by miRanda (www.microRNA.org). 10 miRNAs with highest possibility targeting functional sites of <i>IL-33</i> gene were quantified in cell free plasma samples using a 2<sup>Δ Ct</sup> method. Caenorhabditis elegans miR-39 (cel-miR-39) was used as spike-in control. The results were then log transferd. Carotid plaque (CP) was measured and identified at bilateral common carotid artery, bulb, and proximal internal carotid artery using a high-resolution B mode ultrasound. Receiver-operating characteristic curve (ROC) analysis was performed to determine the discriminating power of the miRNA for the presence of CP. <h3>Results</h3> CPs were identified in 26/76 (34%) subjects (CP+ group). Subjects in the CP+ group were older [58±10 vs 48±11 years old, <i>p</i>=0.001], predominantly male [48 (42.3%) vs 43 (14.0%), <i>p</i>=0.006], with a higher C-reactive protein (CRP) level [24.9±25.0 vs 11.8±13.7 mg/dL, <i>p</i>=0.018] and higher cardiovascular risk [Framingham risk score (FRS): 12.8±11.6 vs 5.7±6.8, <i>p</i>=0.008] (Table 1). All miRNAs were detected in &gt;80% of subjects in both group. Plasma level of miR-186–5p in the CP+ group was significantly higher than that in the CP- group [log miRNA: 3.28±3.21 vs 2.58±1.13 <i>p</i>=0.008]. It was still significant after adjusting age, sex, plasma CRP and FRS (<i>p</i>=0.030) (Table 1). Using multivariate logistic regression, miRNA-186–5p was an independent predictor of the presence of carotid plaque (OR: 1.919, 95% CI=1.096–3.361, <i>p</i>=0.023) after adjustment of FRS and CRP level. [Area under the ROC (AUC) 0.66, 95% CI: 0.60–0.80 <i>p</i>=0.024]. <h3>Conclusions</h3> miR-186–5p was an independent predictor for presence of subclinical atherosclerosis and may serve as a novel biomarker for risk stratification in ERA patients with mild to moderate cardiovascular risk. <h3>Disclosure of Interest</h3> None declared
AB0563 Rituximab in patients with takayasu arteritis: a seven patients experience
Authors: G Pazzola, F Muratore, N Pipitone, F Crescentini, P Cacoub, L Boiardi, L Spaggiari, C Comarmond, S Croci, D Saadoun, C Salvarani
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Takayasu arteritis (TAK) is a large vessel vasculitis involving the aorta and its major branches in patients younger than 40 years. Glucocorticoids (GCs) are the mainstay of treatment for TAK, but relapses and GC dependence are seen in more than two-thirds of patients. Increasing evidence supports a role for B cells in the pathogenesis of TAK. Circulating plasmablasts and memory B cells are increased, while naive B cells are decreased in patients with active TAK as compared with inactive and control patients [1]. These findings suggest a potential role for B cell depleting therapy in TAK. <h3>Objectives</h3> Our aim was to assess the efficacy and safety of Rituximab (RTX) in a series of 7 patients with TAK. <h3>Methods</h3> We conducted an open-label study on 7 TAK patients (5 followed prospectively, 2 retrospective cases) treated with RTX. All patients satisfied the American college of Rheumatology classification criteria for TAK. Six of the 7 patients had a disease refractory to high dose GCs and conventional immunosuppressive (IS) and/or biologic agents. One newly diagnosed, treatment naïve TAK patient refused GCs and received RTX alone. RTX was administered according to rheumatoid arthritis scheme (2 infusions of 1.000 mg, 15 days apart). Clinical evaluation, laboratory tests (full blood count, ESR, CRP) and imaging modalities (CTA or MRA, and PET/CT) were performed at first RTX administration and every 6 months thereafter. Disease activity was assessed using Kerr index. Radiographic disease progression was defined as new or worsening lesions at follow-up CTA or MRA. PET/CT was considered positive for active disease if two or more large vessels showed grade 2 FDG uptake or higher. <h3>Results</h3> Seven patients (6 females) were included in the study. Mean (SD) age was 32.4 (±16.1) years. At first RTX administration, all patients had active disease according to Kerr index (≥2), and had also evidence of active disease at PET/CT. Table 1 summarizes the main results of our study. Despite RTX treatment, 4 of the 7 patients had evidence of persistent disease activity and/or radiographic disease progression during follow-up. Three out of 7 patients in whom RTX was employed as rescue therapy achieved complete remission. <h3>Conclusions</h3> Our data do not support a role for RTX as first line biologic therapy in TAK patients, but it may have a role in some patients as second/third line biological therapy. <h3>References</h3> Hoyer BF et al. Takayasu arteritis is characterised by disturbances of B cell homeostasis and responds to B cell depletion therapy with rituximab. Ann Rheum Dis 2012;71:75–9. doi:10.1136/ard.2011.153007. <h3>Disclosure of Interest</h3> None declared
Letter by Koh Regarding Article, “Potential Deaths Averted and Serious Adverse Events Incurred From Adoption of the SPRINT (Systolic Blood Pressure Intervention Trial) Intensive Blood Pressure Regimen in the United States: Projections From NHANES (National Health and Nutrition Examination Survey)”
Authors: Kwang Kon Koh
Journal: Circulation (2017)

Bress et al 1 estimated the deaths prevented and excess serious adverse events incurred if the SPRINT (Systolic Blood Pressure Intervention Trial) intensive systolic blood pressure (SBP) treatment goal were implemented in all eligible US adults and observed that, if fully implemented in eligible US adults, intensive SBP treatment could prevent ≈107 500 deaths per year; however, a consequence of this treatment strategy could be an increase in serious adverse events.The best therapeutic target of SBP has been debated since the SPRINT study.Recently, the rate of elevated SBP (>110-115 and >140 mm Hg) increased substantially between 1990 and 2015, and these prevalence estimates correspond with a 49% increase in the unadjusted number of annual deaths resulting from an SBP >110 mm Hg and a 51% increase resulting from an SBP >140 mm Hg in 2015. 2 Although the present study evaluated the best SBP target in older hypertensive patients to prevent cardiovascular risk, the issue has not yet been clearly resolved.In older (age ≥65 years) hypertensive patients, intensive SBP control (SBP <140 mm Hg) decreased major adverse cardiovascular events, including cardiovascular mortality and heart failure, but increased the risk of renal failure. 3Weber et al 4 stated earlier that there might be benefits in targeting treatment to below our recommended level of 130 mm Hg in nondiabetic hypertensive patients at high cardiovascular risk (as in the SPRINT population); however, the International Society of Hypertension thinks it is premature to advocate such low targets at a global level.Therefore, the Eighth Joint National Committee took a targeted approach to consideration of previous trials and concluded that SBP targets should be <140 mm Hg and <150 mm Hg in those ≥60 years of age.Physicians should keep in mind that rates of serious adverse events of hypotension, syncope, electrolyte abnormalities, and acute kidney injury or failure, but not of injurious falls, were higher in the intensive treatment group than in the standard-treatment group. 1,3,5When we look closely at this finding, the difference was small (3 mm Hg) in the context of the reduction in BP observed in both arms (13 and 16 mm Hg) because the study did not demonstrate a difference in the unadjusted number of annual deaths between arms. 2,5
Incidental Detection of Hepatocellular Carcinoma on 68Ga-Labeled Prostate-Specific Membrane Antigen PET/CT
Authors: D. Patel, H. Loh, K. Le, A. Stevanovic, R. Mansberg
Journal: Clinical Nuclear Medicine (2017)

A 66-year-old man with history of prostate carcinoma underwent Ga-labeled prostate-specific membrane antigen PET/CT for surveillance of rising prostate-specific antigen. Intense tracer uptake was noted in segments 2, 7, and 8 of the liver. The lesions were not FDG avid on F-FDG PET/CT. Further characterization with magnetic resonance cholangiopancreatography with Gd-EOB (Primovist) contrast revealed ill-defined arterially enhancing lesions with central washout in the venous phase. CT-guided core biopsy was performed, and histopathology confirmed well-differentiated hepatocellular carcinoma.
AB0009 Genomic signatures may be associated with vascular pathology associated with rheumatoid arthritis
Authors: S Poliska, E Végh, A Váncsa, S Szamosi, M Csumita, G Zahuczky, G Szücs, S Szántό, L Nagy, Z Szekanecz
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Accelerated atherosclerosis and cardiovascular (CV) disease have been associated with rheumatoid arthritis (RA). Many genes have been implicated in atherosclerosis, RA or both. However, most of these studies described SNPs in <i>CD40, SMAD3, HLADR, CTLA4</i> and other alleles. Very few studies on genetic signatures have been performed that would link RA and CV pathology. We have previously associated some genomic profiles with pathological carotid atherosclerosis (ccIMT), arterial stiffness (PWV) and brachial artery flow-mediated vasodilation (FMD). In other studies we have also found 165 genes that separated anti-TNF responder patients from non-responders. <h3>Objectives</h3> Here we looked for associations between clinical and "vascular" response to biologics and vascular pathology in RA patients. <h3>Methods</h3> In this study, 19 RA patients were treated with either etanercept (ETN) or certolizumab pegol (CZP) for one year. We separated responders (R) and non-responders (NR) according to EULAR response criteria. Microarray gene expression study was performed (Affymetrix) followed by analysis using the GeneSpring software, hierarchy clustering and principal component analysis (PCA). "Vascular response" (VR) to biologics was defined as an at least 20% improvement in FMD, ccIMT or PWV. Good Vascular Response (GVR) was defined as an at least 20% improvement in two or three of these variables. <h3>Results</h3> Among the 19 patients, 13 were R and 6 were NR. With respect to VR, FMD, ccIMT and PWV responded to anti-TNF treatment in 10, 9 and 8 patients, respectively. GVR was observed in 8 patients and 5 patients had VR in all 3 parameters. When comparing clinical response and VR, 7 out of 8 patients showing GVR also had good clinical response to biologics. Up-regulation of 99 and down-regulation of 67 genes separated clinical R and NR patients. Significant correlation was found between ccIMT improvement upon biological therapy and clinical response (R=0.418, p=0.04). <h3>Conclusions</h3> Genomic signature analysis may be able to separate clinical responders and non-responders to biologics, as well as patients that show or do not show imporvement of vascular pathology. <h3>Disclosure of Interest</h3> None declared
SP0086 Pathogenic memory cells: road blocks to tolerance induction?
Authors: H-D Chang
Journal: Annals of the Rheumatic Diseases (2017)

While conventional state-of-the-art immunosuppression can lead to significant improvement for patients suffering from rheumatic diseases, only in rare cases a therapy-free remission is achieved. In most cases stopping of treatment results in disease relapse. Apparently, components of the immune system are refractory to conventional immunosuppression and can drive the inflammation. Experimental and clinical evidence suggests that cells of the immunological memory persist despite immunosuppression and if pathogenic play a major role in the chronification of the disease. In particular long-lived memory plasma cells secreting autoantibodies represent a major therapeutic challenge. Once generated, they are not subject to physiological and even conventional therapeutic immune regulation. Their elimination may be prerequisite to curative therapies. A detailed understanding the lifestyle of long-lived memory plasma cells will be important to address this cell type therapeutically. <h3>Disclosure of Interest</h3> None declared
France to prosecute its drug regulator and Servier in scandal over diabetes drug
Authors: Owen Dyer
Journal: BMJ (2017)

France’s drug regulator and one of its leading drug companies, Servier, will stand trial as legal persons over the marketing of the antidiabetes and weight loss drug benfluorex (marketed in France as Mediator), which is believed to have killed between 500 and 2300 people before being pulled from the market in 2009.1

Joining them will be nine other institutional defendants, many of them affiliates of Servier, and 14 people, including the company’s former vice president, civil servants, a former senator accused of watering down an official report on the drug, and a professor of paediatrics retained by Servier who is accused of suborning the senator.

Benfluorex is very similar to fenfluramine, a component of the …
OP0315 Reasons for discontinuation of biological agents in patients with juvenile idiopathic arthritis: data from the portuguese register, reuma.pt
Authors: AF Mourão, M Eusébio, J Melo-Gomes, F Oliveira-Ramos, F Martins, P Estanqueiro, M Salgado, M Guedes, M Conde, S Carvalho, J Tavares-Costa, C Duarte, I Brito, C Furtado, A Rodrigues, G Sequeira, R Campanilho-Marques, J Branco, MJ Santos, J Eurico-Fonseca, H Canhão
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Persistence on medication mainly reflects both effectiveness and safety of a drug. Understanding the reasons to stop bDMARD in routine clinical practice can help to better define the efficacy and safety of biologic medications in children with juvenile idiopathic arthritis (JIA). <h3>Objectives</h3> To investigate persistence on treatment and the reasons for discontinuation of the first biological in patients with JIA. <h3>Methods</h3> Portuguese patients with JIA registered in Reuma.pt who started a bDMARD were analyzed. Persistence was defined as the time between treatment initiation and discontinuation of the first bDMARD. The mean time until discontinuation was calculated using Cox regression survival estimates and the reasons for discontinuation of the first bDMARD were registered. <h3>Results</h3> Of the 1724 JIA patients registered in Reuma.pt, 319 received biological therapy, 62% (198) female. The mean age at disease onset was 7.7±4.8 years and the mean time between the beginning of JIA and the first bDMARD was 8.2±9.4 years. The mean disease duration was 13.7±10.7 years and the mean age at the beginning of biological therapy was 15.8±9.4 years. The distribution of JIA subtypes was: 19.1% polyarticular RF-negative, 17.2% enthesitis-related arthritis, 16.6% polyarticular RF-positive, 16% extended oligoarticular, 13.5% persistent oligoarticular, 12% systemic JIA and 0.9% had undifferentiated arthritis. Considering the whole group, 53.2% have had extra-articular manifestations and 18.4% have or had had uveitis since the beginning of the disease. Persistence on treatment, before discontinuation (due to any cause) was 34.7 months (range: 0.03–182 months) adjusted for gender, biological therapy, JIA subtype, age at the beginning of biological therapy, and disease duration until initiating first bDMARD. The major reasons for drug discontinuation was inefficacy (49.6%), remission (14.2%), adverse events (10.6%), patient decision (1.6%) and pregnancy planning (1.4%). In 22.7% the reason was not specified. <h3>Conclusions</h3> Almost half of the JIA patients stop the first biological agent, due to lack of response, reinforcing the need for the existence of several treatment options fully studied in JIA. <h3>Disclosure of Interest</h3> None declared
Invasive mold infections of the central nervous system in patients with hematologic cancer or stem cell transplantation (2000–2016): Uncommon, with improved survival but still deadly often
Authors: Minas P. Economides, Leomar Y. Ballester, Vinodh A. Kumar, Ying Jiang, Jeffrey Tarrand, Victor Prieto, Harrys A. Torres, Dimitrios P. Kontoyiannis
Journal: Journal of Infection (2017)
OP0295 Unique whole blood microrna biosignature for rheumatoid arthritis
Authors: V Anaparti, I Smolik, X Meng, N Mookherjee, H El-Gabalawy
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> RA susceptibility risk is disproportionately high (∼2–3fold) in Indigenous North American (INA) tribes compared to other populations<sup>1,2</sup>. Environmental, lifestyle &amp; genetic factors account for &lt;20% of observed disease variance suggesting contribution of additional risk determinants<sup>3</sup>. Emerging evidence suggests small non-coding microRNAs (miRs) e.g. miR-155, miR-146a, miR-26b are key contributors to RA pathogenesis<sup>4</sup>. In this project, we examined the role of miRs on RA incidence, and association with anti-citrullinated protein antibodies (ACPA), whose appearance precedes disease symptoms. We hypothesized that differential expression of specific miRs associated with disease symptoms will facilitate RA transition in genetically susceptible first-degree relatives (FDRs). <h3>Methods</h3> Whole blood and peripheral blood mononuclear cells (PBMCs) were obtained from age-matched ACPA+ RA patients (n=18), non-symptomatic ACPA+ FDRs (n=12) and ACPA- healthy controls (n=12), who belonged exclusively to INA Cree-Ojibway communities of Northern Manitoba, Canada. Total RNA was isolated using miRVANA kit (Ambion). Expression of selected 32 miRs based on the published literature, and associated downstream mRNA targets, were monitored by quantitative real-time PCR, RNU48 and 18sRNA were used for input normalization for miRNA and mRNA expression respectively. <h3>Results</h3> Whole blood expression profiling identified 10 differentially expressed miRs in RA patients compared to control subjects. Expression of miR-103a-3p was significantly up-regulated (∼2.3-fold; p=0.0062), whereas that of imiR-16, miR-24, miR-29a, miR-125a-3p, miR-203, miR-222, miR-223, miR-150 and miR-346 were down-regulated in RA patients compared to controls. Increased miR-103a-3p expression was also confirmed in PBMCs from ACPA+ RA patients (∼2 fold; p=0.0040) compared to controls. Further, miR-103a-3p expression was increased in ACPA+ FDRs (&gt;4 fold) compared to controls (p=0.0005), and ACPA+ RA patients (p=0.0149). miR-103a-3p expression was consistently elevated in ACPA+ FDRs, when we analyzed samples obtained at two independent time points (1year apart). Consistent with this, expression of AGO1 and DAPK1 mRNA, downstream targets of miR-103a-3p, was decreased significantly (p&lt;0.05) in ACPA+ FDRs compared to controls. <h3>Conclusions</h3> This study defines a unique signature of dysregulated miRs amongst RA patients and their related FDRs within the INA cohort. Our results suggest a potential role of miR-103a-3p as a prognostic biomarker for pre-clinical RA. <h3>References</h3> Barnabe et al J Rheumatol. 2008;35(6):1145–50. Smolik et al J Rheumatol. 2013;40(6):818–24. Viatte et al Nat Rev Rheumatol. 2013;9(3):141–53. Vicente et al Nat Rev Rheumatol. 2016 Apr;12(4):211–20. <h3>Acknowledgements</h3> Canadian Institute of Health &amp; Research (CIHR). <i>Research Manitoba</i> <h3>Disclosure of Interest</h3> None declared
The predictive role of interim PET after the first chemotherapy cycle and sequential evaluation of response to ABVD in Hodgkin’s lymphoma patients—the Polish Lymphoma Research Group (PLRG) Observational Study
Authors: J.M. Zaucha, B. Małkowski, S. Chauvie, E. Subocz, J. Tajer, W. Kulikowski, A. Fijołek-Warszewska, A. Biggi, F. Fallanca, M. Kobylecka, M. Dziuk, D. Woszczyk, J. Rybka, R. Kroll-Balcerzak, F. Bergesio, A. Romanowicz, A. Chamier-Ciemińska, P. Kurczab, A. Giza, K. Leśniewski-Kmak, R. Zaucha, D. Świetlik, T. Wróbel, W. Knopińska-Posłuszny, J. Walewski, A. Gallamini
Journal: Annals of Oncology (2017)