tbuckley/cabot-search huggingface dataset:
Prasugrel or Ticagrelor in ST-Segment–Elevation Myocardial Infarction Patients With Diabetes Mellitus
Authors: Gennaro Sardella, Massimo Mancone, Rocco Edoardo Stio, Erika Cavallo, Angelo Di Roma, Riccardo Colantonio, Simone Calcagno
Journal: Circulation (2017)
False memories, nonbelieved memories, and the unresolved primacy of communication
Authors: Robert A. Nash
Journal: Behavioral and Brain Sciences (2018)

Abstract Mahr &amp; Csibra (M&amp;C) make a compelling case for a communicative function of episodic remembering, but a less compelling case that this is its primary function. Questions arise on whether confirming their predictions would support their account sufficiently, on the communicative function of preserving rich, nonbelieved memories, and on the epistemic benefits of developing false memories via the acceptance of misinformation.
Abstract 17169: Chest Pain Readmission After Percutaneous Coronary Intervention is Common but Not Associated With a Worse Prognosis
Authors: Alfonso Freites, Pablo Salinas, Ester Canovas, Adriana De-La-Rosa, Javier Alonso, Roberto Del-Castillo, Lorenzo Hernando, Ana Huelmos, Javier Botas
Journal: Circulation (2013)

Background:  Readmission rates are currently discussed as a quality outcome. Chest pain readmission after percutaneous coronary intervention (PCI) is challenging and a concern for clinicians. Furthermore, its prognostic implications are poorly understood. The study aims to determine the prognosis of patients discharged after PCI, readmitted for chest pain in the long-term follow-up.   METHODS:  Patients undergoing PCI at our hospital are prospectively followed for at least 12 months. From a total of 746 patients discharged after PCI for any reason between 2007 and 2011, 389 patients were readmitted for any cause (mean age 66.4±11; 84.5% male) after a mean follow-up of 27±0.5 months. We studied baseline clinical characteristics, procedure details and laboratory parameters. During the follow-up we analyzed first readmission incidence, cause of readmission and all-cause mortality. Survival was assessed by Kaplan Meier curves and Log-Rank test for group comparison, and a Cox proportional-hazards model was built for HR adjustment.   RESULTS:  Out of 746 patients, 389 were readmitted (52%), 222 (29.8%) for cardiovascular causes and 181 (24.3%) due to chest pain. Mean time to readmission was 12.8±0.61 months after discharge. Survival in readmitted patients was lower during the follow-up (mean survival 50.7 vs. 53.2 months respectively, p  Chest pain readmitted patients had similar prognosis compared to those without readmission (mean survival 52.3 months vs. 53.22, p=0.48). This may be explained because chest-pain patients were younger, had better LVEF and less prevalence of diabetes and chronic kidney disease. Compared to readmission for other causes, chest pain readmission was associated with lower mortality in the multivariable model adjusted for baseline clinical variables (HR 0.328; 95%CI 0.15 - 0.720).   CONCLUSION:  Long-term all-cause readmission after PCI is associated with a worse prognosis. Readmission for chest pain was frequent but not associated with a worse prognosis compared to readmission for other causes; with similar survival than non-readmitted patients.
03.20 Identification of chromatin modifying mechanisms in inflammatory macrophages in rheumatoid arthritis
Authors: Kelly Rooke, Pal Mander, Laurens Kruidenier, Fernando Martinez, Hussein Al-Mossawi, Paul Bowness, Catherine Swales, Raj Prinjha, Udo Oppermann
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Alterations in epigenetic mechanisms have been implicated in the regulation of pro-inflammatory cytokine production, and bromodomain-containing proteins (the BET family) may have a specific role in the transcriptional regulation of inflammatory genes. Our objective was to examine specific epigenetic variation between the responses of macrophages derived from RA patients and healthy volunteers, and those derived from inflammatory synovial fluid (SF). Delineation of any epigenetic differences between different macrophage populations may highlight new therapeutic targets in inflammatory disease. <h3>Materials and methods</h3> A library of small molecule inhibitors, including BET protein inhibitors, was used to identify key epigenetic regulators of pro-inflammatory cytokine production from macrophages. Macrophages were differentiated from the blood monocytes of normal volunteers and RA patients. Synovial fluid derived macrophages were isolated from RA patients undergoing therapeutic arthrocentesis. Cell culture media was supplemented with a small molecule inhibitor, and lipopolysaccharide subsequently used to stimulate inflammatory cytokine production. Cell viability was confirmed using WST-1 assay, cytokine production was measured using an MSD platform and qPCR to assess gene expression. Each experimental condition was performed in triplicate, alongside positive and negative controls. The study was ethically approved and all samples were obtained with informed consent. <h3>Results</h3> Inhibitors of BET proteins (JQ1, I-BET151 and PFI-1) were the only class of inhibitor to show consistent down-regulation of pro-inflammatory cytokines in both healthy and RA-patient derived macrophages. BET protein inhibitors significantly suppressed the production of TNFα and IL-6 production from RA blood derived macrophages <i>and</i> IL-6 from corresponding SF-derived macrophages. However, only JQ1 achieved significant inhibition of TNFα production from SF-derived macrophages; it also abrogated LPS-induced cytokine and chemokine mRNA expression in the macrophages of patients with RA. <h3>Conclusions</h3> This data suggests that the BET proteins are essential regulators of pro-inflammatory cytokine and chemokine production from the macrophages of patients with RA. The differential response to BET inhibition by macrophages derived from blood and synovial fluid of RA patients could indicate alteration in BET protein distribution at pro-inflammatory cytokine promoters, influenced by the chronic inflammatory environment. This study highlights the therapeutic potential of BET inhibitors (particularly JQ1) in RA. <h3>Funding acknowledgements</h3> NIHR BRU, BBSRC and GlaxoSmithKline
pH応答性アルテミシニンdelivery法,磁気共鳴および光学的重モデル事前画像ガイド下化学/光熱組合せ癌治療のための二重MOFナノ構造の制御可能な合成【Powered by NICT】
Authors: Wang Dongdong, Zhou Jiajia, Chen Ruhui, Shi Ruohong, Zhao Gaozheng, Xia Guoliang, Li Ren, Liu Zhenbang, Tian Jie, Wang Huijuan, Guo Zhen, Wang Haibao, Chen Qianwang
Journal: Biomaterials (2016)
Overexpression of N1-acetylpolyamine oxidase (PAO) in human lung cancer cells alters cellular response to specific antitumor polyamine analogues: Mechanism for drug resistance
Authors: Yanlin Wang, Amy Hacker, Tracy M. Stewart, Patrick M. Woster, Robert A. Casero
Journal: Cancer Research (2005)

5084  The critical nature of polyamines in cell growth and the frequent dysregulation of their metabolism in cancer have led to the targeting of the polyamine metabolic pathway as an antitumor strategy. Importantly, recent molecular characterization of each of the polyamine catabolic enzymes and their potential to profoundly alter drug response has propelled considerable interest into understanding their role in modulating tumor cell sensitivity to the antitumor polyamine analogues. Analogue-induced oxidation of the natural polyamines by PAO and the newly discovered spermine oxidase, SMO(PAOh1), has been implicated in the cytotoxic response of solid tumor types to specific polyamine analogues. But the potential that oxidase activity may lead to drug resistance by detoxifying the antitumor analogues has received less attention. Here we examine the substrate specificity of recombinant human PAO with respect to the natural polyamines and various antitumor analogues and examine the effects of overexpression of human PAO in the analogue-sensitive A549 human lung adenocarcinoma cell line. The results indicate that PAO, in addition to effectively oxidizing N1-acetylspermine and N1-acetylspermidine, also rapidly oxidizes several symmetrically and unsymmetrically substituted antitumor polyamine analogues, including N1, N11-bis(ethyl)norspermine (BENSpm), N1-ethyl-N11-(cyclopropyl)methyl-4,8,diazaundecane (CPENSpm), N1-ethyl-N11-(cycloheptyl)methyl-4,8,diazaundecane (CHENSpm), and (S)-N1-(2-methyl-1-butyl)-N11 -ethyl-4,8,diazaundecane (IPENSpm). When overexpressed in A549 cells, PAO oxidizes each of the analogues, reduces their intracellular accumulation, blocks the downstream apoptotic events common in response to treatment with these agents, and confers significant resistance to each of these compounds. By contrast, the response to representative oligoamine polyamine analogues that are not PAO substrates is not altered by PAO overexpression. These results suggest a mechanism of resistance to specific antitumor polyamine analogues and provide insight into means for improving the design and use of new agents with greater clinical potential.
Single institution retrospective study of infusional etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin, (EPOCH) +/- rituximab (R) as first line therapy for aggressive non-Hodgkin lymphoma.
Authors: Zanetta S. Lamar, Nora Fitzgerald, Jodi Michelle Palmer, Lindsey Gruber, Olga RaetskayaSolntseva, LeAnne Kennedy, Rakhee Vaidya, Kenneth Warren Zamkoff, David Duane Hurd
Journal: Journal of Clinical Oncology (2015)

e19514 Background: Standard treatment for aggressive NHL (aNHL) is R-CHOP in B cell lymphomas and CHOP in T cell lymphomas. A significant proportion of patients; however, ultimately die from their disease. To improve outcomes, novel chemotherapy combinations, dosing schedules and strategies have been used. We describe 136 patients with untreated aNHL treated with infusional dose adjusted EPOCH (DA- EPOCH) chemotherapy +/- R in the first line setting. Methods: We screened 138 patients using the tumor registry. Inclusion criteria included diagnosis of aNHL and first line treatment with EPOCH +/-R given from 2005-2013. Exclusion criteria: primary CNS lymphoma and CTCL not requiring therapy. Results: 136 patients met inclusion criteria. 112 (82%) B-cell and 24 (18%) T-cell NHL. 102 (75%) patients were stage III/IV and 34 (25%) were stage I/II. The median duration of follow up was 27 months and 62 (55%) patients completed six or more cycles. The ORR was 82%. 90 patients achieved CR, (76 B-cell and 14 T-cell); 21 with PR (16 B-cell and 5 T-cell). Using Kaplan Meier estimates, RFS at 1, 3, and 5 years was 68%, 63%, and 52% with 95% CIs [0.59,0.85], [0.54,0.70], and [0.31,0.70], respectively. Of the 136 patients, 65 were dose adjusted per guidelines. 10 (7.4%) died within 30 days of completing treatment and 50 (37%) had at least one cycle of therapy delayed. From univariate logistic regression models predicting death, progression, or relapse at two years, patients with T-cell NHL had increased risk of an event [95% CI = 1.4, 8.8] compared to B-cell NHL. Dose adjustment, delay of chemotherapy, unplanned hospitalization and hematologic or non-hematologic toxicity were not associated with risk of an event with 95% CIs [0.29,1.2], [0.45,1.9], [0.37,1.5], and [0.58,2.4] respectively. In multivariate analysis, current smoking, vincristine capped and need for second line therapy were independent predictors of death or relapse. Conclusions: Our data suggests EPOCH+/-R is active in both B and T aNHL. Toxicity did not significantly delay treatment or negatively impact outcomes. Dose adjustment by nadir had no impact on outcomes.
AB0750 The GO-DACT protocol: a randomized controlled trial to compare the efficacy of golimumab in combination with methotrexate (MTX) versus mtx monotherapy, in improving dactylitis and enthesitis, in MTX NAÏVE psoriatic arthritis patients
Authors: E Vieira-Sousa, H Canhão, JE Fonseca
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Dactylitis is a hallmark manifestation of psoriatic arthritis (PsA) and a key feature for PsA diagnosis. Active dactylitis is associated with a higher risk of erosions and can severely impact function. The therapeutic strategies for dactylitis are however largely empirical, with a profound absence of knowledge regarding efficacy, as primary endpoint, and impact on disease progression. The use of biologic disease modifying anti-rheumatic drugs (DMARDs) in patients with dactylitis, refractory to non-steroidal anti-inflammatory drugs (NSAIDs) or local corticosteroids, is recommended by EULAR guidelines, over the use of conventional DMARDs, based in the scarcity of evidence and properly designed studies in this field. <h3>Methods</h3> GO-DACT is an investigator initiated ongoing multicentric trial, involving 13 national Rheumatology departments. Patients older than 18 years, with the diagnosis of PsA and active dactylitis (tenderness score≥1), refractory to NSAIDs, for 3 months, were included. Patients were randomized on a 1:1 ratio, to either MTX in combination with golimumab or placebo, for a period of 24 weeks. The primary aim of this trial is to determine differences of efficacy between the two treatment arms, in improving dactylitis (and enthesitis), as assessed by the dactylitis severity score (DSS) at 24 weeks. Key secondary outcomes include: Leeds dactylitis index (LDI), Leeds enthesitis index (LEI), joint counts, psoriasis area and severity index (PASI) and nail psoriasis severity index (NAPSI), health assessment questionnaire (HAQ), Dermatology life quality index (DLQI) and composite indexes for disease activity. The effect of treatment arms, on different tissue compartments, will be analysed by contrast-enhanced magnetic resonance imaging (MRI), with high resolution images for dactylitis, at baseline and 24 weeks. <h3>Results</h3> The results from GO-DACT are expected to have implications in clinical practice, bringing robust and valid data for the definition of dactylitis treatment stratification and algorithm.GO-DACT will also contribute to understand dactylitis pathogenesis through the assessment of treatment efficacy, namely in distinct tissue compartments as defined by MRI. https://www.clinicaltrials.gov(NCT02065713) <h3>Acknowledgements</h3> Acknowledgments: This investigator initiated trial was supported by a research grant from Merck Sharp and Dohme <h3>Disclosure of Interest</h3> None declared
Comparison of Two Busulphan-Based Conditioning Regimens Outcomes for Children and Young Adults with Acute Myeloid Leukemia in a Silgle Center in Brazil
Authors: Victor Gottardello Zecchin, Ana Cristina Mendonca, Renata Fittipaldi, Virginio Fernandes, Cintia Monteiro, Adriane Ibanez, Leticia Alves Ribeiro, Adriana Seber, Maria Lucia Martino Lee
Journal: Blood (2016)
AB0101 New mutated peptidylarginine deiminase from porphyromonas gingivalis a target in early ra citrullinates major ra-autoantigens
Authors: M Jenning, B Marklein, J Yetterberg, G Burmester, K Skriner
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Objectives</h3> Previous reports showed that peptidylarginine deiminase (PPAD) form <i>Porphyromonas gingivalis (P.g.)</i> is not able to citrullinate proteins internaly. New mutated PPAD (mPPAD) from <i>P.g.</i> involved in periodontal disease (PD) cloned out of <i>P.g.</i> strain was characterized and analyzed for its reactivity in sera from patients with systemic autoimmune diseases <h3>Methods</h3> We cloned a new enzymatically active recombinant mutated PPAD from <i>P.g. mPPAD</i> mutations and citrullination sites were analyzed by DNA sequencing and/or protein mass spectrometry. Autocitrullination activity it9s enzymatic-activity and human autoantigen protein citrullination was investigated by 2D-Elektrophoresis, MS, immunoblot analysis and ELISA. Furthermore we tested anti-mPPAD/cit-mPPAD with human sera (n=93) from early RA before and after onset of RA (n=30), established RA (n=32), SLE (n=16) and healthy blood donors (n=15) in ELISA assays. To study a potential impact on the RA mouse model (CAIA), mPPAD-containing vesicles from <i>P.g.</i> were injected by intraperitoneal injection (IP). <h3>Results</h3> Recombinant mPPAD lacks 43 amino acids at the N-terminus and exhibits so far two new amino acid mutations (amino acid position 73 (F&gt;L) and 447 (E&gt;V). We were able to demonstrate, mPPAD is enzymatically active over a huge pH-range (3–10) and autocitrullinates at amino acid position 63 the arginine to citrulline. Moreover mPPAd citrullinates major autoantigens in RA (Fibrinogen, Vimentin and hnRNP-A2/B1) which are detectable by RA patient sera and specific anti-citrulline monoclonal antibodies. mPPAD citrullinates HeLa-protein extracts and these specific citrullinated proteins are recognized by RA patient sera. Anti-citrullinated mPPAD antibodies were detected in 41% (n=32) of patients with RA but not in SLE (n=16) and control sera (n=15). In a RA follow-up study (n=30), we detected nearly similar antibody-sensitivities for citrullinated mPPAD before and after onset of RA (13/20%). Only a minority (7%) of RA patients show higher mPPAD antibody levels after RA diagnosis. In the Collagen antibody-induced arthritis (CAIA) RA mouse model mPPAD containing <i>P.g.</i> vesicles when injected IP showed a TLR2-dependent protective anti- inflammatory effect like <i>P.g.</i> LPS and Lipomannan. <h3>Conclusions</h3> Pg. infection and RA disease diagnosis occurs on different timepoints and Pg. infection induces a TLR2-dependent protective anti-inflammatory effect.We show the first time that mPPAD can citrullinate major human autoantigens internally and their immunologically and diagnostic relevance. <h3>Disclosure of Interest</h3> None declared
Blocking and randomization to improve molecular biomarker discovery.
Authors: Li-Xuan Qin, Qin Zhou, Faina Bogomolniy, Liliana Villafania, Narciso Olvera, Magali Cavatore, Jaya Satagopan, Colin B. Begg, Douglas A. Levine
Journal: Journal of Clinical Oncology (2014)

5573 Background: Randomization and blocking have the potential to prevent the negative impacts of non-biological effects on molecular biomarker discovery. Their use in practice, however, has been scarce. Methods: To demonstrate the logistic feasibility and scientific benefits of randomization and blocking, we conducted a microRNA study of endometrial tumors (n=96) and ovarian tumors (n=96) using a blocked randomization design to control for non-biological effects; we profiled the same set of tumors for a second time using no blocking or randomization. We assessed empirical evidence of differential expression in the randomized study and the non-randomized study. We conducted simulation studies to further evaluate the benefits of randomization and blocking on the accuracy of biomarker detection. Results: There was moderate and asymmetric differential expression (10%=351/3,523) between endometrial and ovarian tumors in the randomized dataset. Array effects were observed in the non-randomized dataset and 1,934 markers (55%) were called differentially expressed (DE). Among them, 181 were deemed DE (181/351, 53%) and 1,749 non-DE (1,749/1,934, 90%) in the randomized dataset. In the simulation study, when randomization was applied to all samples at once or within each of multiple batches balanced in sample groups, blocking improved the true positive rate (TPR) from 0.95 to 0.97 and the false positive rate (FPR) from to 0.02 to 0.002. When sample batches are unbalanced, randomization within each batch had a worse TPR (0.92) and FPR (0.10) regardless of blocking. Normalization improved the detection of true positive markers often at the price of increased false positive markers. Conclusions: Through empirical and simulated studies, we showed that blocking and randomization (across all samples or within balanced batches) can effectively improve the accuracy of detecting disease markers. They should be used to more fully reap the benefits of genomics technologies.
02.44 The potential of vault particles to serve as biomarker in rheumatoid arthritis mvp, a novel biomarker of early rheumatoid arthritis
Authors: Dionysia Marinou, Gkikas Katsifis, Maria Mavrouli, Athanassios Tsakris, John Routsias
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Vaults are the largest nonicosahedral cytosolic ribonucleoprotein particles ever described, with a mass of 13Mda. They are ranging from 10<sup>4</sup> to 10<sup>7</sup> particles per cell, with an enormous interior volume, large enough to encapsulate hundreds of proteins or RNAs. Their functions have not been fully elucidated although various studies suggest that they are involved in multidrug resistance, nucleocytoplasmic transport, and intracellular signalling. Vaults are barrel-shaped particles comprising a 78-mer of major vault protein (MVP) molecules, 2 other proteins TEP1 and VPARP and a small untranslated RNA (vRNA). TEP1 shares sequence similarity with Ro autoantigen, a common target of autoantibodies, while vault RNA is complexed with another autoantigen the La protein. In this study, we sought to evaluate the levels of MVP in sera of patients with RA relative to healthy individuals. <h3>Materials and methods</h3> MVP levels were quantified in serum of 46 patients with rheumatoid arthritis, 10 patients with early rheumatoid arthritis (ERA), 17 patients with osteoarthritis (OA) and 22 healthy individuals, using a MVP sandwich ELISA. We also measured the levels of RF, CRP and anti-CCP in the same serums. <h3>Results</h3> MVP levels were found elevated in ERA (100% positive, 89.5% specificity) and RA (73.9% positive, 89.5% specificity), whereas the levels of MVP were found reduced in OA (17.6% positive) and normal subjects (4.5% positive). Notably, 50% of ERA patients were anti-CCP and RF negative and MVP positive. MVP levels were similar in RA and ERA patients but lower from OA patients and normal subjects (p&lt;0.001). MVP levels were strongly correlated with the presence of anti-CCP antibodies (p&lt;0.001) and RF (p&lt;0.001) but not with CRP levels. <h3>Conclusions</h3> MVP levels are remarkably elevated in both patients with RA or ERA, having the potential to serve as a new diagnostic marker for early detection of rheumatoid arthritis.