tbuckley/cabot-search huggingface dataset:
AB0138 Time-Course of Microvascular versus Macrovascular Endothelial Dysfunction in Rat Adjuvant-Induced Arthritis
Authors: P. Totoson, K. Maguin-Gaté, M. Nappey, C. Prati, D. Wendling, C. Demougeot
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Rheumatoid arthritis (RA) is associated with increased risk for cardiovascular disease (CVD). Whereas ample evidence demonstrated the presence of endothelial dysfunction (ED) in RA, it is still unclear how early this abnormality develops. Moreover most of studies have been performed on the macrovasculature but little is known about ED in the microvasculature. <h3>Objectives</h3> The aim of this study is to investigate the time-course of microvascular and macrovascular impairment in adjuvant-induced arthritis (AIA) in rats. <h3>Methods</h3> AIA was induced by an intradermal injection of <i>Mycobacterium butyricum</i> in the tail of male Lewis rats (Day 0). Arthritis severity was evaluated by clinical and radiological analysis at 4 stages of AIA: day 4 (preclinical stage), day 11 (very early arthritis), day 33 (severe disease), day 90 (chronic disease). At each stage, functional and mechanical properties of third-order mesenteric arteries were determined by assessing flow-mediated dilatation, myogenic tone and stress-strain relationship. Macrovascular function was studied on isolated aortic rings in which the contractile response to norepinephrine (NE) and the vasorelaxant response to Acetylcholine (Ach) and to sodium nitroprussiate (SNP) were evaluated. <h3>Results</h3> Macrovascular ED became evident at the severe disease. At the chronic phase of AIA the presence of ED was positively correlated to the radiological score. The response of aortic rings to SNP was normal whatever the stage of AIA. By contrast, NE-induced contractility was significantly reduced in AIA at day 4, and recovered the normal values thereafter. In microvascular bed, ED appears at the early arthritis stage. At the severe disease, microvascular ED is still present and is associated with reduced arterial stiffness. At day 90, one group of microvessels from AIA exhibited ED whereas another group did not, but ED was not correlated to the radiological score. Myogenic tone was unchanged during the course of arthritis. <h3>Conclusions</h3> Our results demonstrated that micro and macrovascular beds are differentially affected during the course of RA. Microvascular ED is a very early event in the course of arthritis. It precedes the occurrence of macrovascular ED and microvascular stiffness. Our data suggest that the measurement of microvascular function would be relevant for the early diagnosis of CV risk in RA patients. They also suggest that mechanisms underlying macro- and microvascular dysfunction are different. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.1687
Abstract 2894: Integrated bioinformatic analysis to elucidate molecular mechanisms associated with reversal of osteosarcoma malignancy induced by CD99.
Authors: Marika Sciandra, Andrea Grilli, Maria Teresa Marino, Maria Cristina Manara, Piero Picci, Katia Scotlandi
Journal: Cancer Research (2013)

Abstract Introduction: CD99 is a transmembrane glycoprotein which is physiologically involved in several biological processes, such as cell migration, adhesion, and differentiation. High levels of CD99 have been reported in mesenchymal stem cells and osteoblasts. In contrast, the molecule has been shown to be absent in osteosarcoma (OS), in which it acts as a tumour suppressor. The molecular mechanisms responsible for its functions are however still poorly defined. In this study we used bioinformatic studies to integrate gene expression and miRNA data to identify crucial mediators. Methods: Forced expression of CD99 was stably induced in Saos-2 OS cell line. Microarray analyses of gene or miRNA expression were performed and integrated by using different bioinformatic approaches. TargetScan, Miranda, Diana-microT and PicTar prediction databases were used to identify miRNA targets. Results: CD99-overexpressing cells displayed a massive down-regulation of gene expression. Only 19 probes were found to be significantly up-regulated in CD99 transfectants compared to parental cells. In contrast, 231 probes were found to be down-regulated, thus suggesting gene modulation by epigenetic mechanisms. We thus examined miRNA profile of these cells. A significant up-regulation of miR-1225-3p, miR-1238, miR-1305, miR-191*, miR-34a, and miR-425* was observed in CD99 overexpressing cells. Enrichment analyses pointed out an involvement of TGFβ signalling. Interestingly, SMAD-2 and -4, which emerged as targets of miR-34a, were among the main down-modulated genes. miR34 mimics confirmed the association between miR34a and SMAD-4. Functional studies are on-going to establish associations with osteosarcoma malignancy. Conclusions: Besides inhibiting osteosarcoma malignancy, CD99 expression in osteosarcoma cells determines massive gene expression repression, likely due to changes in miRNA profile. Up-regulation of miR-34a together with down-regulation of TGFβ signalling mediators seem to be critical players. Studies are granted by AIRC 10452 and Ministry Health RF-2009 to KS. Citation Format: Marika Sciandra, Andrea Grilli, Maria Teresa Marino, Maria Cristina Manara, Piero Picci, Katia Scotlandi. Integrated bioinformatic analysis to elucidate molecular mechanisms associated with reversal of osteosarcoma malignancy induced by CD99. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2894. doi:10.1158/1538-7445.AM2013-2894
SP0197 Screening and assessing cardiovascular risk in inflammatory arthritis
Authors: A. Meadows
Journal: Annals of the Rheumatic Diseases (2013)

The importance of identification of modifiable cardiovascular risk factors in people with inflammatory arthritis is now well established. Several guidelines have been published in recent years to help clinicians implement these in the clinical practice, such as NICE 2009 (79), EULAR (2009) and DOH England (2009). The main challenge in recent years has been to develop a system for screening which incorporates these guidelines in day-to-day clinical practice, working in partnership with the patient as well as primary care clinician. We would like share our experience of cardiovascular health screening in a rheumatology clinic, in Peterborough including a nurse lead clinic, which we have been running over the last 10 years. This talk will describe how we have carried out the screening; it will explain how successful the programme has been and also describe how we have adapted the screening process in response to the results we have obtained so far. <h3>Disclosure of Interest</h3> None Declared
Abstract P2-06-05: Single-cell RNA sequencing of paclitaxol-treated breast cancer cell lines to find individual cell response
Authors: CJ Vaske, W Lee, SC Benz, JZ Sanborn, BM Emerson, N Pourmand, Diaz F Lopez
Journal: Cancer Research (2012)

Abstract Cancer treatments act on a population of cells, each of which may experience different individual responses to treatment. Such differential response will result in resistance to treatment even if a majority of cancerous cells are eliminated. To examine differential cell response, we simultaneously profiled the gene expression and mutation spectrum of individual cells from the MDAMB231 cell line using next generation sequencing of isolated RNA. A total of 23 transcriptomes were characterized from paclitaxel-treated and paclitaxel-surviving cells. We found significant different changes in mutation rates between paclitaxel treated cells, with a dose-dependent increase in single nucleotide changes in RNA in paclitaxel-treated cells. Cells undergoing exposure to paclitaxel also showed higher pathway activity in SRC, as well as an integrin switch from ITGB1 to ITGB3. In contrast, cells that survived a high dose of paclitaxel showed an insignificant number of single nucleotide changes, suggesting that these cells either evaded initial paclitaxel exposure or were better able to repair the effects of paclitaxel exposure. Despite the RNA sequence similarity between surviving and untreated cells, there were changes in gene expression and pathway activities including higher PI3K activity. Paclitaxel-surviving cells also showed activation of pathways associated with higher proliferation. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-06-05.
Abstract 4186: Development of a novel, genetically faithful model of pediatric glioblastoma
Authors: Rebecca A. Ihrie, Emmanuelle Huillard, Claudia Petritsch, David James, Martin McMahon, David H. Gutmann, David H. Rowitch, Arturo Alvarez-Buylla
Journal: Cancer Research (2010)

Abstract Gliomas are among the most lethal human cancers, with high-grade tumors exhibiting a dismal 5-year survival rate. Mutations and amplifications of receptor tyrosine kinases such as PDGFR and EGFR, which drive Ras-MAPK pathway activity, are among the hallmark mutations of adult gliomas. However, pediatric glioblastomas often do not exhibit the oncogenic mutations found in adult tumors, suggesting that these tumors may have distinct mechanistic origins. The unique genetic characteristics of pediatric brain tumors may also affect their response to conventional treatment. Therefore, there is a need to generate mouse models that faithfully recapitulate the genetics of pediatric glioblastomas to identify potential avenues for improving treatment of these tumors. Recent genetic profiling of pediatric brain tumors has found activating mutations of the BRaf kinase in higher grade tumors but not low-grade juvenile pilocytic astrocytomas. By contrast, BRaf is not frequently altered in adult gliomas, suggesting that cells in the developing brain may be particularly susceptible to this mechanism of Ras pathway activation. In addition, BRaf mutation is closely linked to the loss of the tumor suppressor Ink4a/Arf, indicating a possible requirement for loss of this tumor suppressor in the development of high-grade gliomas. Here, we describe the generation of a model system allowing expression of oncogenic BRaf in spatially and temporally defined populations of neural stem cells. In BRaf CA/+; R26YFP animals, Cre-mediated recombination induces expression of the oncogenic V600E mutant form of Braf from the endogenous gene locus and simultaneously labels these cells via expression of YFP. By stereotaxically injecting Cre-expressing adenovirus into the neonatal or adult brain in these mice, we can induce oncogene expression in specific populations of neural progenitors and track its effects on infected cells. Data from multiple tumor types suggests that the activation of Ras-MAPK signaling via BRaf mutation is tightly linked to loss of the Ink4a/Arf tumor suppressor locus. We are also using viral introduction of Cre to activate oncogenic BRaf when Ink4a/Arf expression is absent. The phenotype of these mice will be compared to human pediatric gliomas to determine if this system provides an accurate model of the human disease. Such a model would provide a platform for testing targeted therapies against BRaf - a critical step in designing new treatments for pediatric glioblastoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4186.
ASSOCIATION OF LEFT ATRIAL FUNCTION AND STRUCTURE WITH ELECTROCARDIOGRAPHIC MARKERS OF ATRIAL AND ATRIOVENTRICULAR CONDUCTION ABNORMALITIES IN THE MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA)
Authors: Theingi Tiffany Win, Bharath Ambale Venkatesh, Elsayed Soliman, Larisa Tereshchenko, Colin Wu, Xiaoying Yang, Masamichi Imai, Mohammadali Habibi, Filip Zemrak, Susan Heckbert, David Bluemke, Joao Lima
Journal: Journal of the American College of Cardiology (2016)
Abstract P6-02-08: Molecular drivers of adipogenotoxicosis in breast tumor-associated adipose
Authors: RE Ellsworth, LA Field, R van Laar, B Deyarmin, JA Hooke, CD Shriver
Journal: Cancer Research (2012)

Abstract Background: Having long been thought to function only as an inert energy storage depot, the role of adipose tissue in tumorigenesis has been largely ignored; however, adipose is an active endocrine organ that can directly influence tumor growth. Improved understanding of the role of adipose in tumorigenesis is crucial given the association between obesity and breast cancer risk in post-menopausal women, increasing rates of obesity and use of autologous fat transfer in breast reconstruction. Methods: Adipose, adjacent to and distant from (&amp;gt;3 cm from the closest tumor margin) invasive breast tumors, was laser microdissected from 20 post-menopausal women, and from 22 post-menopausal women with non-malignant breast disease. Gene expression data were generated using U133A 2.0 microarrays. Data were analyzed to identify significant patterns of differential expression between adipose classes at the individual gene and molecular pathway level. Gene expression differences were validated using qRT-PCR in an additional set of 29 specimens. Results: SPP1, RRM2, MMP9 and PLA2G7 were expressed at &amp;gt;3-fold (P &amp;lt; 0.01) higher levels in adjacent adipose compared to distant adipose from the same breast. A number of immune response genes including MARCO, FABP7, ELF5, MYBPC1, MMP7, CLDN8, HLA-DQB1 and HLA-DQA1 were differentially expressed in distant adipose compared to adipose from non-malignant breasts. The most significant gene expression differences were detected between tumor-adjacent and non-malignant adipose with &amp;gt;3-fold higher expression of EGFL6 and ITGB2 and &amp;gt;3-fold lower levels of PIP, which are involved in growth, proliferation, and cellular adhesion in adjacent compared to non-malignant adipose. Pathway analysis revealed that immune response differs between non-malignant, distant and tumor-adjacent adipose with an enhanced B- and T-cell response detected in adjacent compared to distant or non-malignant adipose. Inflammatory response as well as DNA transcription and replication pathways were differentially expressed in distant compared to non-malignant adipose. Conclusions: Gene expression levels differ in breast adipose depending on presence of and proximity to tumor cells. Adipose adjacent to the tumor demonstrated the largest immune response, supporting the idea of adipogenotoxicosis, which through pro-inflammatory and genotoxic responses, promotes tumor development. In addition, genes involved in cellular proliferation, degradation of the extracellular matrix and angiogenesis are differentially expressed in adjacent compared to distant or non-malignant adipose, thus tumor-adjacent adipose may be contributing to the growth and invasion of the primary tumor. These data thus suggest that adipose is not an inert component of the breast microenvironment but plays an active role in tumorigenesis. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-02-08.
AB1256 Outcome of ultrasound guided cortisone injection in patients with rheumatoid arthritis and hypothyroidism
Authors: F.A. Vreju, P. Ciurea, A. Rosu, M. Ciurea
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Carpal Tunnel Syndrome (CTS) is a relatively frequent condition in rheumatoid arthritis (RA), but we should be aware of the connection between carpal tunnel syndrome (CTS) and hypothyroidism.The carpal tunnel is the fibroosseous space between the carpal bones and the flexor retinaculum. It contains 8 flexor tendons, the flexor pollicis longus tendon and occasionally a persistent median artery. CTS is the result of compression of the median nerve within this contained space. <h3>Objectives</h3> The objectives of the study were to assess the outcome of ultrasound guided cortisone injection in patients with rheumatoid arthritis and hypothyroidism. <h3>Methods</h3> The study included 35 patients – 25 with known rheumatoid arthritis and 10 with hypothyroidism who received a local corticosteroid injection for carpal tunnel syndrome. All patients underwent a bilateral carpal tunnel US examination. The CSA (cross-sectional area) of the median nerve was measured at the carpal tunnel and at the level of the pronator quadratus muscle, and the difference between them (ΔCSA) was calculated for each wrist. All carpal tunnel syndromes were diagnosed usingof a ΔCSA threshold of 2 mm<sup>2</sup> rule. <h3>Results</h3> After 1 month, most patients improved, but after 12 months 23 patients (65.71%) – 20 with rheumatoid arthritis and 3 with hypothyroidism, had surgery. Patients with a successful outcome (no need for additional treatment) had a lower median nerve ultrasonographic cross-sectional area (CSA) at the flexor retinacullum, a lower swelling ratio, and a lower symptom severity score (VAS). Most of the patients with hypothyroidism improved after injection and hormone replacement therapy. <h3>Conclusions</h3> Lower swelling ratio measured by ultrasonography may indicate a less severe carpal tunnel syndrome, which is more likely to respond to treatment with a corticosteroid injection. More than this, patients with hypothyroidism are more likely to have a better outcome without surgery. <h3>Disclosure of Interest</h3> None Declared
FRI0146 The risk of gastrointestinal perforations in patients with rheumatoid arthritis treated with anti-TNF therapy - results from the british society for rheumatology biologics register (BSRBR):
Authors: J. Zavada, M. Lunt, R. Davies, A.S. Low, L.K. Mercer, J.B. Galloway, K.D. Watson, D.P. Symmons, K. Hyrich
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> To evaluate the risk of gastrointestinal perforation (GIP) in subjects with RA treated with anti-TNF therapy compared to non-biological disease-modifying antirheumatic drugs (nbDMARDs). <h3>Methods</h3> The analysis was conducted in the British Society for Rheumatology Biologics Register (BSRBR), a prospective cohort study. Patients with RA starting treatment with the TNF inhibitors etanercept (ETA), infliximab (INF) or adalimumab (ADA) and a biologic-naïve comparison cohort exposed to nbDMARDs were recruited between 2001-2009. Subjects were followed until 31/3/2011 or death, whichever came first. Events were ascribed to anti-TNF if they occurred while the patient was receiving anti-TNF therapy or within 90 days of the first missed dose. Events were attributed to the most recent drug received in patients who switched anti-TNF therapy. Cox proportional hazards model were developed to compare the rates of GIP between cohorts. A propensity score was used to balance covariates between treatment groups and included age, gender, weight, comorbidity, smoking, indexes of disease severity, use of steroids, NSAIDs, and gastroprotective drugs. Stratification by deciles of propensity score for treatment was used to adjust for confounding between the groups. Current steroid use was entered into the model as a time-varying covariate. <h3>Results</h3> There were 58 (upper: 25, lower: 33) GI perforations: 5 in the nbDMARD cohort, 37 in the anti-TNF cohort (on drug + 90 days), and 16 in the anti-TNF cohort (off drug). In univariate analyses higher HAQ, history of hypertension, and smoking were associated with the risk of lower GIP, and use of nonselective NSAIDs at baseline and low weight with the risk of upper GIP, irrespective of anti-TNF exposure. After adjustment, treatment with TNF antagonists was associated with hazard ratio (HR) of 1.6 (95% CI 0.4 to 6.0) for all perforations, 2.7 (95% CI 0.4 to 18.1) for lower and 0.9 (95% CI 0.1 to 5.8) for upper GI perforations. Current use of steroids was the single most important predictor of GIP with adjusted HR of 2.9 (95% CI 1.5 to 5.4), but this increase of risk was confined to lower GIPs (HR 8.0, 95% CI 2.6 to 24.1). <h3>Conclusions</h3> Anti-TNF therapy was not associated with statistically significant increase of all GI perforations, although there was a signal of possible increased risk of lower GI perforations. Current use of steroids was the single most important risk factor for lower GI perforations. <h3>Disclosure of Interest</h3> None Declared
The law of unintended consequences
Authors: S Sundar
Journal: Journal of the Royal Society of Medicine (2013)

The medical innovation bill being proposed by Lord Saatchi is laudable in its intentions.1 But the medical innovation bill runs the risk of further embedding the practice of defensive medicine by setting out even more legal criteria that could expand the scope of legally defined medical negligence.

Furthermore, the distinction between clinical research with no direct benefit to patient and innovative treatment intended to benefit the patient is an artificial one. Hence, the laudable aims of medical innovation bill are likely to run foul of the EU clinical trials directive.

The EU clinical trials directive, which initially set out with the commendable aims of promoting research and protecting patients, ended up stifling academically led, innovative, cutting edge research. The mountains of paperwork essential for demonstrating compliance with EU clinical trials directive choked off the seeds of innovation.2,3

The cancer researchers would be grateful if Lord Saatchi and peers could devote their energies to removing the yoke of EU directive on small, academically led, innovative studies.