tbuckley/cabot-search huggingface dataset:
Inhibition of HER2 Increases JAGGED1-dependent Breast Cancer Stem Cells: Role for Membrane JAGGED1
Authors: Deep Shah, Debra Wyatt, Andrew T. Baker, Patricia Simms, Daniel S. Peiffer, Michelle Fernandez, Emad Rakha, Andrew Green, Alexandra Filipovic, Lucio Miele, Clodia Osipo
Journal: Clinical Cancer Research (2018)

Purpose: HER2-positive breast cancer is driven by cells possessing stem-like properties of self-renewal and differentiation, referred to as cancer stem cells (CSC). CSCs are implicated in radiotherapy, chemotherapy resistance, and tumor recurrence. NOTCH promotes breast CSC survival and self-renewal, and overexpression of NOTCH1 and the NOTCH ligand JAGGED1 predict poor outcome. Resistance to anti-HER2 therapy in HER2+ breast cancer requires NOTCH1, and that combination of trastuzumab and a gamma secretase inhibitor (GSI) prevents tumor relapse in xenograft models.Experimental Design: The current study investigates mechanisms by which HER2 tyrosine kinase activity regulates NOTCH-dependent CSC survival and tumor initiation.Results: Lapatinib-mediated HER2 inhibition shifts the population of HER2+ breast cancer cells from low membrane JAGGED1 expression to higher levels, independent of sensitivity to anti-HER2 treatment within the bulk cell population. This increase in membrane JAGGED1 is associated with higher NOTCH receptor expression, activation, and enrichment of CSCs in vitro and in vivo Importantly, lapatinib treatment results in growth arrest and cell death of JAGGED1 low-expressing cells while the JAGGED1 high-expressing cells continue to cycle. High membrane JAGGED1 protein expression predicts poor overall cumulative survival in women with HER2+ breast cancer.Conclusions: These results indicate that higher membrane JAGGED1 expression may be used to either predict response to anti-HER2 therapy or for detection of NOTCH-sensitive CSCs posttherapy. Sequential blockade of HER2 followed by JAGGED1 or NOTCH could be more effective than simultaneous blockade to prevent drug resistance and tumor progression. Clin Cancer Res; 24(18); 4566-78. ©2018 AACR.
SP0136 Last advances in treatment and management of osteoarthritis
Authors: M. Kloppenburg
Journal: Annals of the Rheumatic Diseases (2018)

<h3></h3> Osteoarthritis is a highly prevalent disease that results in a considerable disease burden for patients that suffer from this disease. Osteoarthritis can affect any joint, but is especially prevalent in the knee, hips and hands. The management for osteoarthritis includes non-pharmacological, pharmacological and surgical options. But options depend on the location of osteoarthritis, since not all treatment options are equally effective for patients with different osteoarthritis phenotypes. Fortunately, the number of high-quality clinical trials has increased in the last years and have increased our insight in potential effective treatments for osteoarthritis. Non-pharmacological options include information and education, exercise possibly in combination with weight reduction in overweight patients with knee osteoarthritis or assistive technology in patients with hand osteoarthritis. Regarding effective pain alleviating medication research, including systematic reviews, network analyses and randomised clinical trials, has increased our insight in the clinical efficacy of different medications. This has led to the discussion about the role of acetaminophen in osteoarthritis. New pain alleviating medication has been developed and is currently investigated. Furthermore, currently used medication is investigated for alternative ways of application. The ultimate requirement to have a disease modifying drug available is not yet met, but studies have been undertaken and are ongoing to investigate disease modifying potential. <h3>Disclosure of Interest</h3> None declared
CD300c costimulates IgE-mediated basophil activation, and its expression is increased in patients with cow's milk allergy
Authors: Olatz Zenarruzabeitia, Joana Vitallé, Iñigo Terrén, Ane Orrantia, Itziar Astigarraga, Leire Dopazo, Carlos Gonzalez, Laura Santos-Díez, Carlos Tutau, Pedro M. Gamboa, Agurtzane Bilbao, Francisco Borrego
Journal: Journal of Allergy and Clinical Immunology (2018)

Basophils express high-affinity IgE receptors (FcεRI), which play an essential role in allergic diseases. It is important to characterize new cell-surface receptors that modulate IgE-mediated basophil activation threshold to design promising immunomodulatory therapies.We sought to analyze the expression of CD300 receptors on human basophils and their implication in IgE-mediated basophil activation processes.Blood samples from healthy subjects and patients with cow's milk allergy were collected through the Basque Biobank under an institutional review board-approved protocol. PBMCs were obtained by means of density centrifugation, basophils were purified with a specific isolation kit, and phenotypic and functional studies were performed by using flow cytometry.We demonstrate that basophils express the activating receptor CD300c, which is specifically upregulated in response to IL-3. CD300c works as a costimulatory molecule during IgE-mediated basophil activation, as shown by a significant increase in degranulation and cytokine production when basophils are activated in the presence of CD300c cross-linking compared with activation through the IgE/FcεRI axis alone. Coligation of FcεRI and CD300c increased intracellular calcium mobilization and phosphorylation of signaling intermediates evoked only by FcεRI ligation. We show that the natural ligands of CD300c, phosphatidylserine and phosphatidylethanolamine, modulate IgE-mediated basophil activation. Furthermore, we have observed that CD300c expression in children with cow's milk allergy is increased compared with that in healthy control subjects and that the intensity of expression correlates with the severity of the hypersensitivity symptoms.CD300c could be considered a biomarker and therapeutic target in patients with IgE-mediated allergic diseases because it seems to be involved in the modulation of IgE-mediated basophil activation.
AB0297 Predictors of an inadequate response to treatment in latin american patients with early rheumatoid arthritis
Authors: R.V. Gamboa-Cárdenas, M. Ugarte-Gil, L. Massardo, M.P. Sacnun, A. Granel, L. Catoggio, F.A. Lima-Corrêa, S. Appenzeller, A. Azevedo, M. Keiserman, J. Rueda, L. Zurita, M. Moreno, M. Cardiel, E. Acevedo-Vasquez, G.S. Alarcón, B. Pons-Estel
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Inadequate response to treatment in early rheumatoid arthritis (RA) is associated with adverse consequences. We have previously shown high baseline levels of disease activity in Latin American RA patients.<sup>1</sup> <h3>Objectives</h3> To identify the baseline predictive factors of inadequate response to treatment in patients with early RA from a GLADAR cohort, at one year from cohort entry. <h3>Methods</h3> GLADAR cohort includes 1093 consecutive RA patients with disease &lt;1 year from 46 centres in 14 Latin American countries. For these analyses, patients with complete clinical and laboratory assessments with DAS28-ESR&gt;3.2 at the baseline, and one-year follow up visits were included. Inadequate treatment response was ascertained with the EULAR definition which is based on DAS28-ESR obtained at one-year of follow up [a variation ≤0.6 in any category of activity (mild, moderate or severe) and a variation &gt;0.6 but≤1.2 in the high activity category]. Gender, age at diagnosis, diagnosis delay, socioeconomic status (by the Graffar scale), ethnicity, medical coverage, rural origin, rheumatoid factor (RF) positivity, disability (HAQ-DI), DMARDs use, corticosteroid use, and DMARD treatment delays were examined as potential predictive factors of this outcome. Univariable and multivariable binary logistic regression models, using a stepdown technique were examined in order to determine the predictors of response at 1 year. <h3>Results</h3> Four hundred and forty-eight patients were included. Three hundred and eighty-five (85.9%) were female; the mean (SD) age at diagnosis was 46.1 (13.6) years; 78.3% had medical coverage and 347 patients (77.5%) were RF positive. The mean baseline DAS28-ESR was 6.3 (1.4). EULAR response was met by 347 (77.5%) patients at 1 year. Three hundred patients (67%) have received glucocorticoids, 78.8% at least one DMARD and only 1.1% had received at least one biologic compound. The baseline HAQ-DI was 1.5 (0.0–3.0). Predictors of non-EULAR response at 1 year were: female gender (OR=2.4; CI:1.0–5.6; p=0.039), a higher baseline HAQ-DI (OR=1.7; CI:1.2–2.4; p=0.003) whereas protective factors were higher DAS28-ESR (OR=0.6; CI:0.4–0.7; p&lt;0.001) and having medical coverage (OR=0.5; CI:0.3–0.9; p=0.025). <h3>Conclusions</h3> We have identified baseline predictors of adverse response to treatment in LA patients with early RA. Absence of medical coverage seems to be an additional adverse factor associated with poor results. Other factors such as early response/remission or adherence to treatment should be taken into account. <h3>Reference</h3> [1] Massardo L. Arthritis Care Res (Hoboken)2012;64(8):1135–4. <h3>Disclosure of Interest</h3> None declared
OP0100 Increase in direct healthcare costs in juvenile idiopathic arthritis over the past 10 years – results of a health insurance claims data analysis
Authors: I. Redeker, F. Hoffmann, K. Albrecht, J. Klotsche, A. Zink, K. Minden
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Biological disease-modifying anti-rheumatic drugs (bDMARDs) are effective but expensive treatment options in juvenile idiopathic arthritis (JIA). The extent to which the healthcare costs of JIA have changed as a result of their increasing use has hardly been investigated. <h3>Objectives</h3> The aim of this study was to analyse resource utilisation and direct healthcare costs in patients with JIA since the introduction of treatment with biologic agents. <h3>Methods</h3> Using health insurance claims data in Germany, resource utilisation and direct healthcare costs of children and adolescents with a diagnosis of JIA (International Classification of Diseases, Tenth Revision, [ICD-10] code M08, M09.0, L40.5) between January 1, 2007 and December 31, 2016 were assessed. Direct healthcare costs comprised costs for outpatient care (i.e., visits to physicians, laboratory tests, emergency department visits, and outpatient hospital services), costs for inpatient care (i.e., hospital admissions), costs for pharmacotherapy and other treatment costs (i.e., non-physician visits [e.g., visits to physical therapists] and aids/adaptations). <h3>Results</h3> Data from 12 652 children and adolescents with a diagnosis of JIA were included in the analyses. Mean direct healthcare costs per patient increased by 33% from € 4577 in 2007 to € 6109 in 2016. Pharmacological treatment was the cost domain with the highest increase (table 1). This increase was almost entirely caused by an increasing prescription of bDMARDs (from 8.6% to 15.7%). Costs for inpatient care also increased, whereas other treatment costs slightly decreased. Total costs per patient were calculated as the sum of the domains outpatient care, hospital admissions, pharmacotherapy and other treatment costs. bDMARDs, biological Disease-Modifying Anti-Rheumatic Drugs; csDMARDs, conventional synthetic Disease-Modifying Anti-Rheumatic Drugs. * excluding costs for pharmacotherapy. <h3>Conclusions</h3> Direct healthcare costs in JIA considerably increased over the past 10 years, mainly caused by an expanding use of biologic agents. The results also showed that the rise in costs for treatment with biologic agents has been at a plateau since 2014. The healthcare costs incurred must, of course, always be placed in the context of indirect and intangible costs and the long-term prognosis of patients. <h3>Acknowledgements</h3> This work was supported by the Federal Ministry of Education and Research within the research network PROCLAIR (01EC1405). <h3>Disclosure of Interest</h3> None declared
SAT0274 Retention rates of certolizumab pegol in ankylosing spondylitis and non-radiographic axial spondyloarthritis patients: hur-bio real life results
Authors: B. Armagan, A. Sari, A. Erden, G.K. Yardimci, L. Kilic, U. Kalyoncu, O. Karadag, S. Apras Bilgen, S. Kiraz, A. Akdogan, I. Ertenli
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Drug survival rate is generally accepted as a reliable indicator of both efficacy and safety profile of a biological DMARD. <h3>Objectives</h3> To evaluate survival rates of certolizumab-pegol (CZP) in ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nrAxSpA) patients registered in HUR-BIO (Hacettepe University Rheumatology Biologic Registry). <h3>Methods</h3> HUR-BIO is a monocentric database of biologics including 2058 SpA patients (226 were prescribed CZP) by June 2017. All AS (n=142) and nrAxSpA (n=54) patients in HUR-BIO prescribed CZP at least once were enrolled in the study. Twenty-three patients who was already on CZP before admitting Hacettepe University were excluded. Patients prescribed CZP within 6 months period before analysis defined as drug continuing. Demographic, clinical and laboratory data of AS and nrAxSpa patients were evaluated. Kaplan-Meier analysis was used to estimate CZP survival rates. <h3>Results</h3> In total, 124 AS and 49 nrAxSpA patients were analysed. Baseline characteristics of patients were shown in Table. Median duration of CZP usage was 7.54 (3–26.5) months in AS and 6.27 (3–26.7) months in nrAxSpA group(p=0.53). CZP survival was similar between AS and nrAxSpA patients (figure 1). Fourty-nine (27.2%) patients had used at least one TNFi and 38 (21.9%) patients had used more than one TNFi before CZP. There was no difference in drug survival between those who used TNFi and those who did not use TNFi before CZP (figure 2). BASDAI 50 response was reached in 27.6% of AS and 36.0% of nrAxSpA patients and at the last control visit (p=0.44). <h3>Conclusions</h3> In this single centre biological SpA cohort, adherence to CZP therapy seems to be high with a first year survival rate of 83% and there was no difference between AS and nrAxSpA patients. <h3>Disclosure of Interest</h3> None declared
Evidence of Prostate-Specific Membrane Antigen Expression in Metastatic Differentiated Thyroid Cancer Using 68Ga-PSMA-HBED-CC PET/CT
Authors: Priyanka Verma, Gaurav Malhotra, Ritesh Agrawal, Sunita Sonavane, Vilas Meshram, Ramesh V. Asopa
Journal: Clinical Nuclear Medicine (2018)

Purpose of the Report Prostate-specific membrane antigen (PSMA) overexpression is not restricted to prostate cancer, but it has also been demonstrated in gliomas, lung cancer, and in tumor neovasculature. Systematic studies exploring PSMA uptake in thyroid tumors are lacking. The aim of this pilot study was to assess PSMA expression in patients with metastatic differentiated thyroid cancer (mDTC). Materials and Methods Ten patients of mDTC harboring 32 lesions (5 men; age range, 38–65 years; mean age, 50 years) underwent prospective evaluation with radioiodine ( 131 I), 18 F-FDG PET, and 68 Ga-PSMA-HBED-CC PET scans as per the institution protocol. PSMA expression (SUV max ) was compared with 18 F-FDG and 131 I scan findings in all patients. Results Lesions were radioiodine avid in 8 patients, whereas 2 were classified as thyroglobulin elevation with negative iodide scintigraphy (TENIS) patients. All patients with iodine-avid metastatic disease showed substantial PSMA uptake. PSMA PET detected 30/32 total lesions (93.75%; SUV max ranging from 4.86 to 101.81 with median SUV max of 31.35), whereas FDG PET/CT was positive in 23/32 lesions (81.85%). Twenty-one (70%) of 30 lesions that showed PSMA expression were localized to the bones. PSMA localized a lesion in each of the 2 TENIS patients similar to FDG PET scan. Conclusions 68 Ga-PSMA-HBED-CC PET/CT is a potentially useful imaging modality in patients of mDTC with most (70%) of PSMA expressing metastasis being localized to the bones. PSMA PET/CT could be useful for identifying patients with limited therapeutic options (eg, TENIS) who might benefit from PSMA-targeted radionuclide therapy.
Uncoupling ITIM receptor G6b-B from tyrosine phosphatases Shp1 and Shp2 disrupts murine platelet homeostasis
Authors: Mitchell J. Geer, Johanna P. van Geffen, Piraveen Gopalasingam, Timo Vögtle, Christopher W. Smith, Silke Heising, Marijke J. E. Kuijpers, Bibian M. E. Tullemans, Gavin E. Jarvis, Johannes A. Eble, Mark Jeeves, Michael Overduin, Johan W. M. Heemskerk, Alexandra Mazharian, Yotis A. Senis
Journal: Blood (2018)
Abstract 11875: Risk of Malignant Cancer Among Women With New-onset Atrial Fibrillation
Authors: David Conen, Jorge A Wong, Roopinder K Sandhu, Nancy R Cook, I-Min Lee, Julie E Buring, Christine M Albert
Journal: Circulation (2015)

Introduction: A substantial proportion of patients with atrial fibrillation (AF) die of non-cardiovascular causes, and recent studies suggest a link between AF and cancer. However, this association has not been evaluated in long-term prospective studies. Methods: A total of 34691 women ≥45 years and free of AF, cardiovascular disease and cancer at baseline were prospectively followed for incident AF and malignant cancer within the Women’s Health Study. All incident AF and cancer events were validated by medical record review. Cox proportional-hazards models using time-updated covariates were constructed to assess the relationship of new-onset AF with incident cancer and to adjust for potential confounders. We then assessed the risk of incident AF among women with cancer using a similar modelling approach. Results: Mean age at baseline was 55±7 years. During 19.1 years of follow-up, we observed 1467 (4.2%) AF and 5130 (14.8%) cancer events. AF was a significant risk factor for incident cancer in age-adjusted (hazard ratio (HR) 1.58, 95% confidence interval (CI), 1.34, 1.87, p&lt;0.0001) and multivariable adjusted (HR 1.49, 95% CI, 1.26, 1.77, p&lt;0.0001) models, and was increased among women with paroxysmal (HR 1.35, 95% CI 1.09, 1.67, p=0.005) and non-paroxysmal AF (HR 1.61, 95% CI 1.23, 2.09, p=0.0004). The risk of cancer was highest in the first 3 months after new-onset AF (HR 3.53, 95% CI 2.05, 6.08, p&lt;0.0001) but remained significant beyond 1 year (adjusted HR 1.44, 95% CI 1.19, 1.73, p=0.0001). New-onset AF was also associated with an increased risk of cancer mortality (adjusted HR 1.37, 95% CI 1.01, 1.85, p=0.04). In contrast, women with new-onset cancer had an increased risk of incident AF within 3 months (HR 4.61, 95% CI 2.81, 7.54, p&lt;0.0001) but not beyond 1 year (HR 1.17, 95% CI 0.97, 1.41, p=0.11). Conclusions: In this large cohort of initially healthy women, new-onset AF was a significant risk factor for the short and long term diagnosis of incident cancer. In contrast, cancer was not associated with an increased AF risk over the long term. Our results may suggest that AF could be an early sign of occult cancer or an underlying systemic process conferring an increased cancer risk.
AB0897 The relationship between disease-specific indices and balance in patients with ankylosing spondylitis
Authors: Y. Acar, N. İlçin, B. Gürpınar, G. Can, F. Önen
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Axial and periferal joint stifness, impaired joint mobility and postural deformities may affect balance in AS. However factors affecting balance in AS patients are still unclear. There is limited literature investigating balance-related factors in patients with AS and the results are contradictory. <h3>Objectives</h3> The aim of the study was to investigate relationship between disease-specific indices and balance in patients with AS. <h3>Methods</h3> 72 patients(46 male, 26 female) with AS were included in the study. The demographic and anthropometric features(age, weight, height, body mass ındex(BMI)) of patients were recorded. Disease-specific indices used in the study were Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI) and Bath Ankylosing Spondylitis Mobility Index (BASMI). BASDAI for disease activity, BASFI for functional capacity, BASMI for spinal mobility were used. Static and dynamic balance was evaluated with Biodex Balance System SD. Limits of stability and bilateral stance (stable and unstable platform), single leg stance (stable platform) postural stability test results were recorded. Overall stability(OA) indices were used. A high score in the OA index indicates poor balance. Spearman correlation test used for statistical analysing. Correlation analyses were performed between BASDAI, BASFI, BASMI scores and Biodex test results <h3>Results</h3> The mean age of patients was 39,95±8,84 years and mean BMI was 26,55±3,82 kg/m<sup>2</sup>. BASDAI, BASFI and BASMI scores of patients are shown in table 1. Only positive weak correlation was found between BASFI score and right leg stance overall postural stability index (r=0,25, p=0,034). No other correlation was detected between BASDAI, BASFI, BASMI scores and Biodex balance test results. <h3>Conclusions</h3> The results of our study indicated that there is no relationship between BASDAI, BASFI, BASMI scores and balance except BASFI score and right leg stance postural stability. Our results contradict some previous studies while supporting some studies. This may be due to in our study BASDAI, BASFI and BASMI scores are lower than previous studies or the usage of different methods from previous studies for evaluating balance and postural stability in AS. Further studies are required to establish the actual status of relationship between balance and clinic measurements in AS patients. <h3>Reference</h3> [1] Pompeu, J.E., Static and dynamic balance in subjects with ankylosing spondylitis: literature review. Revista brasileira de reumatologia, 2012. 52(3): p. 413–416. <h3>Disclosure of Interest</h3> None declared
Sleep apnoea in the asymptomatic elderly: a real issue for the brain?
Authors: Sébastien Celle, Claire Boutet, Cédric Annweiler, Jean-Claude Barthélémy, Frédéric Roche
Journal: European Respiratory Journal (2018)

The link between sleep apnoea and brain structure is unclear; although dysfunction of the hippocampus, middle temporal gyrus and brainstem/cerebellum have been observed previously. However, this link has been little explored in elderly subjects. The aim of this study was to explore the link between sleep apnoea and the brain in an elderly population. 226 asymptomatic elderly subjects (age mean± sd 75.3±0.9 years, range 72.3–77.8 years) from the PROOF (Evaluation of Ageing, Autonomic Nervous System Activity and Cardiovascular Events) cohort study were explored using linear voxel-based or cortical thickness with apnoea/hypopnoea index (AHI; mean± sd 15.9±11.5 events·h −1 , range 6–63.6 events·h −1 ) as a covariate of main interest. The brain volumes of 20 control subjects, 18 apnoeic (AHI &gt;29 events·h −1 ) treated patients and 20 apnoeic untreated patients from this population were compared using voxel-based morphometry, cortical thickness or surface-based analyses. AHI was not associated with any change in local brain volume, cortical thickness or cortex surface. Control subjects, apnoeic treated and untreated patients were not different in terms of local brain volume, cortical thickness or surface. In a specific population of asymptomatic elderly healthy subjects, sleep apnoea does not seem to be associated with a change in local brain volume or in cortical thickness.