tbuckley/cabot-search huggingface dataset:
Abstract 12903: Low-molecular Weight Heparin Improves Endothelial Function in Pregnant Women at High-risk of Preeclampsia
Authors: Kelsey McLaughlin, Dora Baczyk, Audrey Potts, Michelle Hladunewich, John Parker, John Kingdom
Journal: Circulation (2016)

Introduction: Women who develop preeclampsia (PE) demonstrate cardiovascular abnormalities during pregnancy and postpartum. Low-molecular weight heparin (LMWH) significantly reduces the incidence of PE, although the mechanisms of action are unknown. Hypothesis: LMWH improves cardiovascular function in pregnant women at high-risk of PE. Methods: Pregnant women at high-risk of PE (n=25) and low-risk pregnant controls (n=20) at 22-26 weeks’ gestation underwent cardiovascular assessments. High-risk women were then randomized to LMWH or saline placebo (30mg IV bolus and 1mg/kg subcutaneous dose). Cardiovascular function was assessed 1 and 3 hours post-randomization. The in vitro endothelial effects of patient serum and LMWH on human umbilical venous endothelial cells (HUVEC) were determined through angiogenesis assays, gene expression and protein secretion. Results: High-risk women demonstrated a low-volume, high resistance hemodynamic profile with significantly impaired radial artery flow-mediated dilation (FMD) when compared to low-risk controls (6.5±0.9% vs 9.7±1.0%, P=0.03). Baseline plasma and urine levels of placental growth factor (PlGF) were significantly lower in high-risk women compared with controls (P=0.003 and P=0.01, respectively). LMWH significantly increased FMD in high-risk women following randomization compared to baseline (10.8±1.0% vs 7.6±1.0%, P=0.008). LMWH also significantly increased plasma levels of PlGF, soluble fms-like tyrosine kinase-1 and myeloperoxidase (P=0.006, P=0.03 and P=0.03, respectively). Serum from high-risk women significantly impaired HUVEC angiogenesis and significantly increased PlGF-1 and PlGF-2 transcription compared to serum from controls (0.79±0.05 vs 0.99±0.05, P=0.03; P=0.03 and P=0.01, respectively). Co-exposure of high-risk serum with LMWH improved the in vitro angiogenic response such that it was equivalent to that of control serum and promoted PlGF secretion. Conclusions: Our data indicate that LMWH improves maternal endothelial function in pregnant women at high-risk of developing PE, possibly mediated through increased PlGF bioavailability. Future trials are needed to assess the effectiveness of LMWH for the prevention of severe PE in screen-positive women.
SP0131 Autoimmune atherosclerosis
Authors: Z Szekanecz
Journal: Annals of the Rheumatic Diseases (2017)

Arthritides have been associated with accelerated atherosclerosis to increased vascular disease risk. Traditional risk factors, as well as the role of systemic inflammation including cytokines, chamokines, proteases, autoantibodies, adhesion receptors and others have been implicated in the development of these vascular diseases. Accelerated atherosclerosis and increased cardio- and cerebrovascular morbidity and mortality have been observed in rheumatoid arthritis (RA) and spondyloarthropathies (SpA). Endothelial dysfunction, overt atherosclerosis and vascular stiffness may be indicated by brachial artery flow-mediated vasodilation (FMD), common carotid intima-media thickness (ccIMT) and aortic pulse-wave velocity (PWV), respectively. These abnormalities have been described in most inflammatory rheumatic diseases. While ccIMT and stiffness are relatively stable, FMD may be influenced by many confounding factors. In addition to traditional vasculoprotection, immunosuppressive agents including corticosteroids, traditional and biologic DMARDs may have significant vascular and metabolic effects. The official EULAR recommendations on the assessment and management of cardiovascular disease in arthritides have been published. <h3>Disclosure of Interest</h3> None declared
THU0123 New perspectives in diagnosis of interstitial lung disease related to rheumatoid arthritis. validation study of an electronic stethoscope and ad hoc software for detection of pulmonary crackles
Authors: A Manfredi, M Sebastiani, G Cassone, AL Fedele, V Venerito, M Trevisani, F Furini, O Addimanda, E Gremese, F Iannone, G Della Casa, S Cerri, G Sandri, F Pancaldi, F Luppi, C Ferri
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovial joint swelling and tenderness, secondary to the immune-system dysfunction, often complicated by extra-articular manifestations. Among them, lung involvement is very frequent and interstitial lung disease (ILD) represents one of the deleterious complications of RA with impact on both therapeutic approach and overall prognosis. Nevertheless, diagnosis of ILD often remains missing or delayed. <h3>Objectives</h3> To preliminarily evaluate the predictive value of pulmonary sound recorded by an electronic stethoscope (ES) and elaborated by an ad hoc software in identification of RA-ILD diagnosed by mean of high resolution computed tomography (HRCT) in a multicenter study. <h3>Methods</h3> RA patients who underwent HRCT in the last 12 months were enrolled. They were all auscultated with the ES (Littmann 3200<sup>TM</sup> 3M, USA), bilaterally, at dorsal level, in at least 3 pulmonary fields (medium and basal). All tracks recorded were analyzed by a suitably developed software capable of recognizing pathological crackles in lung sounds. Results were compared with radiologic findings detected in a blind manner by an expert radiologist. <h3>Results</h3> One hundred and six RA patients were enrolled (M/F: 1/2.5, mean age 68.7±10.3); among them 45 (42.5%) showed ILD at HRCT. Three patients were excluded because of a low quality of the sound recorded. The algorithm showed a sensitivity and specificity of 72.1% and 84.4%, respectively and a positive/negative predictive value of 69.1% and 86.3%, respectively. <h3>Conclusions</h3> Despite preliminary, these data suggest an important role of ES in clinical practice for an early diagnosis of ILD in RA patients and a significant reduction of inappropriate prescription of HRCT. Since very different types of ILD can occur in course of RA, with different radiologic features and localization, proper development of the measurement setup (ES and ad hoc software for the detection of PC) could further increase its predictive value, in particular to avoid incorrect records and misdiagnosis. The routinely employment of ES and proper software, combined to clinical findings (cough, dyspnea) and respiratory lung function, could increase our ability to early identify ILD in RA patients. <h3>Disclosure of Interest</h3> None declared
Adenosine A2B Receptor Promotes Erythrocyte Oxygen Release to Counteract Tissue Hypoxia and Injury
Authors: Zhangzhe Peng, Renna Luo, Anren Song, Kaiqi Sun, Hong Liu, Yujin Zhang, Morayo G. Adebiyi, Yang Xia, Rodney E. Kellems, Aji Huang
Journal: Blood (2016)
A Transposon Screen Identifies Loss of Primary Cilia as a Mechanism of Resistance to SMO Inhibitors
Authors: Xuesong Zhao, Ekaterina Pak, Kimberly J. Ornell, Maria F. Pazyra-Murphy, Ethan L. MacKenzie, Emily J. Chadwick, Tatyana Ponomaryov, Joseph F. Kelleher, Rosalind A. Segal
Journal: Cancer Discovery (2017)

Abstract Drug resistance poses a great challenge to targeted cancer therapies. In Hedgehog pathway–dependent cancers, the scope of mechanisms enabling resistance to SMO inhibitors is not known. Here, we performed a transposon mutagenesis screen in medulloblastoma and identified multiple modes of resistance. Surprisingly, mutations in ciliogenesis genes represent a frequent cause of resistance, and patient datasets indicate that cilia loss constitutes a clinically relevant category of resistance. Conventionally, primary cilia are thought to enable oncogenic Hedgehog signaling. Paradoxically, we find that cilia loss protects tumor cells from susceptibility to SMO inhibitors and maintains a “persister” state that depends on continuous low output of the Hedgehog program. Persister cells can serve as a reservoir for further tumor evolution, as additional alterations synergize with cilia loss to generate aggressive recurrent tumors. Together, our findings reveal patterns of resistance and provide mechanistic insights for the role of cilia in tumor evolution and drug resistance. Significance: Using a transposon screen and clinical datasets, we identified mutations in ciliogenesis genes as a new class of resistance to SMO inhibitors. Mechanistically, cilia-mutant tumors can either grow slowly in a “persister” state or evolve and progress rapidly in an “aggressive” state. Cancer Discov; 7(12); 1436–49. ©2017 AACR. See related commentary by Goranci-Buzhala et al., p. 1374. This article is highlighted in the In This Issue feature, p. 1355
Declaration of Faith
Authors: Lawrence J. Hergott
Journal: Annals of Internal Medicine (2017)

Ad Libitum19 September 2017Declaration of FaithLawrence J. Hergott, MDLawrence J. Hergott, MDFrom Center for Bioethics and Humanities, University of Colorado School of Medicine, Denver, Colorado.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M17-0576 Audio Reading - “Declaration of Faith” Audio. Virginia L. Hood, MD, Annals Associate Editor, reads "Declaration of Faith," by L.J. Hergott. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail I believe inThe Power of Love,Democracy,andScience—in that order. Author, Article, and Disclosure InformationAffiliations: From Center for Bioethics and Humanities, University of Colorado School of Medicine, Denver, Colorado.Current Author Address: Lawrence J. Hergott, MD; e-mail, [email protected]net. PreviousarticleNextarticle Advertisement Audio Reading - “Declaration of Faith” Audio. Virginia L. Hood, MD, Annals Associate Editor, reads "Declaration of Faith," by L.J. Hergott. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics 19 September 2017Volume 167, Issue 6Page: 435 ePublished: 19 September 2017 Issue Published: 19 September 2017 Copyright & PermissionsCopyright © 2017 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Increased intracellular proteolysis reduces disease severity in an ER stress–associated dwarfism
Authors: Lorna A Mullan, Ewa J Mularczyk, Louise H Kung, Mitra Forouhan, Jordan Ma Wragg, Royston Goodacre, John F Bateman, Eileithyia Swanton, Michael D Briggs, Raymond P Boot-Handford
Journal: Journal of Clinical Investigation (2017)

The short-limbed dwarfism metaphyseal chondrodysplasia type Schmid (MCDS) is linked to mutations in type X collagen, which increase ER stress by inducing misfolding of the mutant protein and subsequently disrupting hypertrophic chondrocyte differentiation. Here, we show that carbamazepine (CBZ), an autophagy-stimulating drug that is clinically approved for the treatment of seizures and bipolar disease, reduced the ER stress induced by 4 different MCDS-causing mutant forms of collagen X in human cell culture. Depending on the nature of the mutation, CBZ application stimulated proteolysis of misfolded collagen X by either autophagy or proteasomal degradation, thereby reducing intracellular accumulation of mutant collagen. In MCDS mice expressing the Col10a1.pN617K mutation, CBZ reduced the MCDS-associated expansion of the growth plate hypertrophic zone, attenuated enhanced expression of ER stress markers such as Bip and Atf4, increased bone growth, and reduced skeletal dysplasia. CBZ produced these beneficial effects by reducing the MCDS-associated abnormalities in hypertrophic chondrocyte differentiation. Stimulation of intracellular proteolysis using CBZ treatment may therefore be a clinically viable way of treating the ER stress-associated dwarfism MCDS.
P2Y <sub>2</sub> Nucleotide Receptor Prompts Human Cardiac Progenitor Cell Activation by Modulating Hippo Signaling
Authors: Farid G. Khalafalla, Steven Greene, Hashim Khan, Kelli Ilves, Megan M. Monsanto, Roberto Alvarez, Monica Chavarria, Jonathan Nguyen, Benjamin Norman, Walter P. Dembitsky, Mark A. Sussman
Journal: Circulation Research (2017)

Autologous stem cell therapy using human c-Kit+ cardiac progenitor cells (hCPCs) is a promising therapeutic approach for treatment of heart failure (HF). However, hCPCs derived from aged patients with HF with genetic predispositions and comorbidities of chronic diseases exhibit poor proliferative and migratory capabilities, which impair overall reparative potential for injured myocardium. Therefore, empowering functionally compromised hCPCs with proregenerative molecules ex vivo is crucial for improving the therapeutic outcome in patients with HF.To improve hCPC proliferation and migration responses that are critical for regeneration by targeting proregenerative P2Y2 nucleotide receptor (P2Y2R) activated by extracellular ATP and UTP molecules released following injury/stress.c-Kit+ hCPCs were isolated from cardiac tissue of patients with HF undergoing left ventricular assist device implantation surgery. Correlations between P2 nucleotide receptor expression and hCPC growth kinetics revealed downregulation of select P2 receptors, including P2Y2R, in slow-growing hCPCs compared with fast growers. hCPC proliferation and migration significantly improved by overexpressing or stimulating P2Y2R. Mechanistically, P2Y2R-induced proliferation and migration were dependent on activation of YAP (yes-associated protein)-the downstream effector of Hippo signaling pathway.Proliferation and migration of functionally impaired hCPCs are enhanced by P2Y2R-mediated YAP activation, revealing a novel link between extracellular nucleotides released during injury/stress and Hippo signaling-a central regulator of cardiac regeneration. Functional correlations exist between hCPC phenotypic properties and P2 purinergic receptor expression. Lack of P2Y2R and other crucial purinergic stress detectors could compromise hCPC responsiveness to presence of extracellular stress signals. These findings set the stage for subsequent studies to assess purinergic signaling modulation as a potential strategy to improve therapeutic outcome for use of hCPCs in patients with HF.
AB0186 ASCA (anti-saccharomyces cerevisae antibody) in scleroderma
Authors: A Fedrigo, TAFG dos Santos, A Bortoluzzi, T Skare, R Nisihara
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> The majority of Scleroderma (SSc) patients have gastrointestinal involvement. Motility is usually compromised but few studies address permeability changes in the intestinal wall. ASCA is an antibody direct against mannan in the cell wall of Saccharomyces cerevisiae, the baker9s yeast that is found mainly when the small bowel is involved in Chron9s disease. Nowadays ASCA is regarded more as a marker of increased gastrointestinal permeability than as a serological autoimmune marker of intestinal inflammatory disease. ASCA levels (anti-Sacharomyces Cerevisae antibodies) are associated with increased intestinal permeability. <h3>Objectives</h3> At present we study the presence of ASCA in the serum of SSc patients aiming to know if there is increased intestinal permeability in this disease and if this is related to any clinical, demographic and treatment data. <h3>Methods</h3> Seventy four SSc patients and 57 healthy controls were studied for ASCA (IgG and IgA) positivity by ELISA. ASCA positivity was associated with demographic, clinical, severity index (Medsger score) and serological data in SSc patients. <h3>Results</h3> ASCA IgG levels were high in 26/74 (43.7%) patients from SSc group and 1/57 (5.2%) of controls (p&lt;0.001); IgA ASCA was high in 12/74 (16.2%) from SSc group and 3/57 (1.7%) of controls (p=0.006). In univariated analysis IgG ASCA high levels associated positively with African background (p&lt;0.0001) and negatively with anticentromere antibodies (p=0.013); ASCA IgA had a negative association with Medsger score (p=0.05). In multivariated analysis IgG ASCA associated independently only with African ethnic background. <h3>Conclusions</h3> Positivity for IgG and IgA ASCA are higher among scleroderma patients than controls. African descendants have more positivity for IgG ASCA and ASCA IgA were less commonly seen in patients with more severe disease. <h3>References</h3> Sallam H, McNearney TA, Chen JD. Systematic review: pathophysiology and management of gastrointestinal dysmotility in systemic sclerosis (scleroderma). Aliment Pharmacol Ther. 2006; 23: 691–712. Cobden I, Rothwell J, Axon ATR, Dixon MF, Lintott DJ, Rowell NR. Small intestinal structure and passive permeability in systemic sclerosis. Gut. 1980; 21:293–8. Ghoshal UC, Ghoshal U, Singh H, Tiwari S.Anti-Saccharomyces cerevisiae antibody is not useful to differentiate between Crohn9s disease and intestinal tuberculosis in India. J Postgrad Med. 2007; 53:166–70. Assessment of intestinal permeability and orocecal transit time in patients with systemic sclerosis: analysis of relationships with epidemiologic and clinical parameters. Rheumatol Int. 2003; 23:226–30. Catanoso M, Lo Gullo R, Giofré MR, Pallio S, Tortora A, Lo Presti M, et al. Gastro-intestinal permeability is increased in patients with limited systemic sclerosis. Scand J Rheumatol. 2001; 30: 77–81. <h3>Disclosure of Interest</h3> None declared
FRI0622 A retrospective cohort study about the clinical characteristics of igg4-related diseases
Authors: X Wu, C Wang, Y Miao, Y Huang, L Dong
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Immunoglobulin (Ig) G4-related disease (IgG4-RD) is an increasingly recognized systemic autoimmune disease in the past decade, and encompasses a wide spectrum of disorders previously considered to be unrelated, but with common pathologic, serologic, and clinical features.There have been several hundred literatures on IgG4-RD published in the past few years, however, we still cannot well characterize this complicated disease, including clinical features, treatments as well as mechanisms, which promotesus to further describe this disease. <h3>Objectives</h3> To describe the clinical presentations, laboratory features, imaging manifestations, treatments and evolutions in a cohort of 34 Chinese patients with immunoglobulin G-related diseases (IgG4-RD). <h3>Methods</h3> A retrospective study was performed in Wuhan Tongji Hospital. Electronically stored records of clinical, laboratory, imaging, and histological features were reviewed. The diagnoses were made according to comprehensive diagnostic criteria for IgG4-RD. Disease activity was assessed by IgG4-RD Responder Index (RI).This study was approved by the Ethical Committee of TongjiHospital (TJ-C20150603). All patients were contacted, and consents were obtained from all the participants. <h3>Results</h3> We found that among the whole 34 patients enrolled in this study (median age=51 years, male/female ratio=1.4/1), 65.2% tested patients had a declined HDL level, 82.3% tested patients had an elevated IgG4 level, and lymph node was the most frequently involved organ. 18F-FDG PET/CT had high sensitivity in providing information about the organ distribution of IgG4-RD. The IgG4 level and IgG4-RD RI in the multi-organs affected patients were significantly higher than that in the localized ones. Most patients were prescribed with glucocorticoids (GCs) alone or combined with disease modifying antirheumatic drugs (DMARDs), the majorities responded well, while some relapsed. Patients given rituximab (RTX) obtained good responses. <h3>Conclusions</h3> It was concluded that 18F-FDG PET/CT can be an effective tool to detect involved lesions of IgG4-RD. The addition of DMARDs to the initial GCs therapy in the remission induction stage may not bring much benefit. The most appropriate dosage schedule of RTX needs to be further investigated. Patients with younger age, longer duration of disease, higher IgG4 level and IgG4/IgG ratio may more commonly experience recurrence. <h3>References</h3> Hamano H, Kawa S, Horiuchi A, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med, 2001,344(10):732–738. Islam AD, Selmi C, Datta-Mitra A, et al. The changing faces of IgG4-related disease: Clinical manifestations and pathogenesis. Autoimmun Rev, 2015,14(10):914–922. Martinez-de-Alegria A, Baleato-Gonzalez S, Garcia-Figueiras R, et al. IgG4-related Disease from Head to Toe. Radiographics, 2015,35(7):2007–2025. <h3>Disclosure of Interest</h3> None declared
A clinically applicable strategy to concurrently profile prostate cancer (PCa) in circulation and bone using high-definition single cell analysis (HD-SCA).
Authors: Amado J. Zurita, Anders Carlsson, Madelyn S. Luttgen, Kelly Bethel, Patricia Troncoso, Paul Gettys Corn, Anand Kolatkar, James B Hicks, Christopher Logothetis, Peter Kuhn
Journal: Journal of Clinical Oncology (2016)

5041 Background: The bone is the most significant organ site to characterize advanced PCa, but repeated bone biopsies are not feasible. Clinically relevant differences may exist between PCa clones in tissue and circulation, especially during therapy. To concurrently characterize tumor cells in blood (CTC) and bone in a clinically feasible manner, we adapted the HD-SCA platform to bone marrow aspirates (BMA). Methods: Peripheral blood and BMAs were obtained from individual patients with biochemically recurrent (BRPC; n = 52), metastatic hormone-naïve (mCSPC; n = 26) and metastatic castration-resistant (mCRPC; n = 63) PCa, before treatment or progressing on therapy. Eleven mCSPC and 59 mCRPC patients had bone metastasis. HD-SCA is a non-enrichment-based platform that allows for quantification of cell morphometry, protein expression and single cell genomic and proteomic analyses. Candidate tumor cells were defined as DAPI+/CK+/CD45-. Androgen receptor (AR) protein expression was also examined in single/clustered tumor cells. Clusters were defined as ≥ 2 tumor cells in direct contact, and their presence was correlated with survival outcomes. Whole genome copy number profiles (CNV) were obtained from single cancer cells. Results: Tumor cells were detected in 26% mCSPC and 39% mCRPC BMAs, while all BMAs from BRPC patients were negative. BMA status was concordant with corresponding BM biopsies (per clinical pathology assessment), but detection in BMAs was 45% more sensitive. Tumor cell clusters were more frequent, abundant and bigger in BMAs than in blood, expressed higher levels of AR per tumor cell, and were prognostic in mCRPC (both for progression-free and overall survival). Analysis of CNV profiles revealed distinct clonal patterns and distribution in BMA/blood from 3 patients with tumor cells present in both compartments. Conclusions: Our strategy allows for concurrent high-content profiling of CTCs and bone metastatic deposits in PCa patients. The simultaneous evaluation of the two liquid compartments resulted in novel insights into the prevalence and clinical significance of tumor cell clusters and clonal heterogeneity in advanced disease.