tbuckley/cabot-search huggingface dataset:
Abstract 3626: Development of inhibitors of the fibroblast growth factor receptor (FGFR) kinase using a fragment based approach
Authors: Matthew S. Squires, Timothy Perera, Gordon Saxty, Chris Murray, Peter King, George Ward, Ruth Feltell, Sharna Rich, Patrik Angibaud, Edward J. Lewis, Ron Gilissen, Isobel Harada, Lynsey Fazal, Julie A. Irving, Mike A. Batey, Yan Zhao, David R. Newell, Neil T. Thompson
Journal: Cancer Research (2010)

Abstract Recent data in a number of tumour types has implicated Fibroblast Growth Factor (FGF) and Fibroblast Growth Factor receptor (FGFR) signalling as being key to the molecular pathology of cancer. FGFR is a receptor tyrosine kinase which activates the extracellular signal-regulated kinase / mitogen-activated protein kinase and the protein kinase B / Akt pathways which promote cell growth and survival. Amplification, over-expression or activating mutations of fibroblast growth factor receptors have been associated with bladder tumours, multiple myeloma, hormone-refractory prostate cancer and breast cancer. Multiple lead series of FGFR inhibitors were developed using Astex's fragment based medicinal chemistry approach, Pyramid™, linked to high throughput X-ray Crystallography. We describe here the characterisation of some examples of these lead molecules. In particular we detail the pharmacological profile of a compound from one of these lead series that demonstrated activity against FGFR 1-4 with an IC50 &amp;lt;100nM in an isolated kinase assay. This compound inhibited FGFR1-4 kinase activity in BaF3 cell lines engineered to express the relevant kinase fusion proteins and proliferation and survival of a panel of FGFR-dependent human tumour cell lines derived from several different tissues. The cytotoxic activity was &amp;gt;10 fold lower in cell lines lacking FGFR expression. We demonstrate inhibition of FGFR 2 and 3 phosphorylation in gastric and multiple myeloma cell lines respectively with associated inhibition of downstream signalling pathways. This lead molecule has an excellent pharmacokinetic profile and high oral bioavailibility in mice and rats. In xenograft models in mice where aberrant FGF signalling underlies tumour pathology, tumour growth inhibition is observed at doses of 100mg/kg /day orally for 21 days. This xenograft efficacy was observed in several models, with significantly lower activity in models where aberrant FGF signalling is not involved in tumour pathology. This suggests that the mechanism of action is consistent with FGFR inhibition. The pharmacological profile in these models is also distinct from other broader spectrum receptor tyrosine kinase inhibitors. The pre-clinical data shown here suggests that such compounds warrant further investigation pre-clinically and may benefit patients whose disease is driven by FGFR activity. 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 3626.
P352High cholesterol diet deteriorates cardiac autophagy
Authors: Z Giricz, ZV Varga, C Csonka, G Szucs, A Adameova, RA Gottlieb, RM Mentzer, P Ferdinandy
Journal: Cardiovascular Research (2014)

Introduction: We have previously shown that autophagy is necessary for the ischemic preconditioning (IPC) of the heart and that IPC is compromised in the setting of hypercholesterolemia (HC). The mTOR pathway, an upstream modulator of autophagy, has been shown to be activated in HC. The purpose of this study was to test the hypothesis that HC results in down regulation of autophagy due in part to activation of mTOR signalling and to investigate whether HC modulates programmed cell death mechanism such as apoptosis and necroptosis in the heart.
P0335 : Serum long chain ceramides, sphingosine and sphingosine-1-phosphate as novel diagnostic markers in patients with hepatocellular carcinoma
Authors: G. Grammatikos, N. Schoell, N. Ferreiros, D. Bon, E. Herrmann, H. Farnik, S. Zeuzem, B. Kronenberger, O. Waidmann, J. Pfeilschifter
Journal: Journal of Hepatology (2015)
THU0279 Absence of radiographic progression of hip arthritis in patients with ankylosing spondylitis treated with infliximab for 6 years
Authors: M. Konsta, V.K. Bournia, P.P. Sfikakis, D. Karras, A. Iliopoulos
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Hip involvement is the most frequent extraspinal arthritic manifestation of Ankylosing Spondylitis (AS) and a common cause of disability. In contrast to the classical changes in the spine, hip joint inflammation does not lead to formation of new bone but results in bone erosions, indicating that at different sites parallel osteoproliferative and osteodestructive changes may occur. Current evidence suggests that anti-TNF treatment does not inhibit radiographic progression in the spine; whether it affects the progression of hip joint space narrowing in AS patients with hip arthritis is not known. <h3>Objectives</h3> To examine the impact of continuous long-term treatment with the anti-TNF antibody infliximab on radiographic progression of hip arthritis in AS patients. <h3>Methods</h3> Twenty-three consecutive patients with AS and hip involvement (21 men, median age of 45 years) prior to the initiation of infliximab treatment were included in this retrospective study. Infliximab was given as monotherapy in 21 and combined with methotrexate in 2 patients. Anteroposterior X-rays of the pelvis obtained at baseline were compared to X-rays obtained after 5.9±2.2 years (mean±SD) of continuous infliximab treatment (5 mg/kg, every 2 months), using: a) the Bath AS radiology hip index (BASRI-h) scoring system (min 1, max 4), a reliable, disease-specific, sensitive to change method for grading hip radiographic change in AS, and b) the width of the whole joint space estimated by measurement of 3 distinct points of interbone distance (2mm inner of the external end of the acetabulum, vertical line through femoral head center, head-neck center line) with the help of a graduated eyepiece. One senior rheumatologist (A.I.) and one rheumatology fellow (M.K.) performed a blinded radiographic review of 23 X-ray pairs. Intraobserver and interobserver reliability was established using intraclass correlation coefficients (ICC). <h3>Results</h3> Both readers achieved excellent agreement for BASRI-h scores and the three points of intraarticular distance (ICC=0.88, 95% CI:0.85, 0,91). The mean±SD BASRI-h score at baseline was 2.50±0.87 and remained unchanged at follow-up end (2.50±0.88). Moreover, the width of the whole joint space at baseline (3.49±0.6 mm) was not reduced after 5.9±2.2 years of infliximab treatment in these patients (3.50±0.74 mm). <h3>Conclusions</h3> Despite the lack of a control group our results suggest that long term infliximab treatment inhibits radiographic progression of hip arthritis in responding patients with AS, possibly by blocking a local osteodestructive TNF-mediated effect. <h3>Disclosure of Interest</h3> None Declared
Treatment of Hereditary Angioedema with a Vapor-Heated C1 Inhibitor Concentrate
Authors: A. Thomas Waytes, Fred S. Rosen, Michael M. Frank
Journal: New England Journal of Medicine (1996)

Hereditary angioedema results from a congenital deficiency of functional C1 inhibitor and is characterized by episodic bouts of edema, which may be life-threatening when they involve the larynx. We evaluated the effectiveness of a C1 inhibitor concentrate in the prevention and treatment of attacks of hereditary angioedema. The concentrate was vapor-heated to inactivate hepatitis and human immunodeficiency viruses.
Discrepancy between Self-Reported and Actual Caloric Intake and Exercise in Obese Subjects
Authors: Steven W. Lichtman, Krystyna Pisarska, Ellen Raynes Berman, Michele Pestone, Hillary Dowling, Esther Offenbacher, Hope Weisel, Stanley Heshka, Dwight E. Matthews, Steven B. Heymsfield
Journal: New England Journal of Medicine (1992)

Some obese subjects repeatedly fail to lose weight even though they report restricting their caloric intake to less than 1200 kcal per day. We studied two explanations for this apparent resistance to diet — low total energy expenditure and underreporting of caloric intake — in 224 consecutive obese subjects presenting for treatment. Group 1 consisted of nine women and one man with a history of diet resistance in whom we evaluated total energy expenditure and its main thermogenic components and actual energy intake for 14 days by indirect calorimetry and analysis of body composition. Group 2, subgroups of which served as controls in the various evaluations, consisted of 67 women and 13 men with no history of diet resistance.
Effect of a Diet Enriched with Monounsaturated or Polyunsaturated Fatty Acids on Levels of Low-Density and High-Density Lipoprotein Cholesterol in Healthy Women and Men
Authors: Ronald P. Mensink, Martijn B. Katan
Journal: New England Journal of Medicine (1989)

Polyunsaturated fatty acids are thought to lower the serum cholesterol level more effectively than monounsaturated fatty acids. It is unclear whether the difference — if any — is due to a lowering of the level of high-density lipoprotein (HDL) or low-density lipoprotein (LDL) cholesterol. We therefore placed 31 women and 27 men on a mixed natural diet rich in saturated fat (19.3 percent of their daily energy intake from saturated fat, 11.5 percent from monounsaturated fat, and 4.6 percent from polyunsaturated fat) for 17 days. For the next 36 days, they received a mixed diet with the same total fat content, but enriched with olive oil and sunflower oil ("monounsaturated-fat diet": 12.9 percent saturated fat, 15.1 percent monounsaturated fat, and 7.9 percent polyunsaturated fat) or with sunflower oil alone ("polyunsaturated-fat diet": 12.6 percent saturated fat, 10.8 percent monounsaturated fat, and 12.7 percent polyunsaturated fat). The serum LDL cholesterol level decreased by 17.9 percent in those on the monounsaturated-fat diet and by 12.9 percent in those on the polyunsaturated-fat diet (95 percent confidence interval for the difference between the effects of the two unsaturated-fat diets, -9.9 percent to 0.0 percent). In men, the HDL cholesterol level fell slightly but not significantly with both diets. In women, the HDL cholesterol level did not change with either. We conclude that a mixed diet rich in monounsaturated fat was as effective as a diet rich in (n-6)polyunsaturated fat in lowering LDL cholesterol. Both diets lowered the level of HDL cholesterol slightly in men but not in women. (N Engl J Med 1989; 321:436–41.)
Tumorigenicity of Human Mesothelial Cell Line Transfected With EJ-ras Oncogene
Authors: R. R. Reddel, L. Malan-Shibley, B. I. Gerwin, R. A. Metcalf, C. C. Harris
Journal: JNCI Journal of the National Cancer Institute (1989)

We performed this study to determine whether human mesothelial cells are capable of undergoing neoplastic change in vitro and to observe their interaction with the activated c-Ha-ras (HRAS1) oncogene EJ-ras, which has a role in the development of many malignant human tumors. Mesothelial cells are presumed to be the progenitor cells of malignant mesothelioma, a cancer strongly correlated with asbestos exposure. Previously, we established a non-tumorigenic cell line, MeT-5A, from normal human mesothelial cells after transfection with a plasmid containing the simian virus 40 (SV40) early-region genes. In the present study, we performed transfection of a plasmid containing the EJ-ras gene and the neomycin-resistance gene into these cells and selected a population resistant to G418, a neomycin analogue. Cells from this cell line formed rapidly growing sc tumors in NIH Swiss athymic nude mice, but untransfected MeT-5A cells and cells transfected with the vector DNA and selected for G418 resistance formed no tumors. The tumors formed by EJ-ras-transfected cells were established in vitro, and cells from these tumor cell lines exhibited a characteristic altered morphology. The cells had the same isoenzyme pheno-type as the parent cells, and they expressed the mutant EJ-ras p21 protein. This first demonstration of malignant transformation of human mesothelial cells in vitro may permit molecular analysis of mesothelial carcinogenesis. [J Natl Cancer Inst 81:945-948, 1989]
PERI-OPERATIVE ELAFIN FOR ISCHAEMIA REPERFUSION INJURY DURING CORONARY ARTERY BYPASS GRAFT/ CARDIAC SURGERY
Authors: Shirjel Alam, Vipin Zamvar, Renzo Pessotto, Lewis Steff, Marc Dweck, Moore Colin, Scott Semple, Oliver Wiedow, Nicholas Mills, Anoop Shah, Colin Stirrat, Saeed Mirsadraee, David Newby, Peter Henriksen
Journal: Journal of the American College of Cardiology (2015)
Differentiated Thyroid Carcinoma
Authors: Amr Amin, Ahmed Badwey, Sherif El-Fatah
Journal: Clinical Nuclear Medicine (2013)

Well-differentiated thyroid cancer (WDTC) is rising in incidence across the world over the past 3 decades. We aimed to evaluate the natural history and clinical outcome of differentiated thyroid carcinoma by a retrospective analysis of 249 patients treated at a single institution.A cohort of 249 patients who underwent thyroidectomy for WDTC in the last 10 years in Maadi Military Hospital was studied. Main outcome measures were clinical management at the diagnosis, survival, morbidity, and prognostic risk factors.Mean age at diagnosis was 44.7 (SD, 14.6) years, where 52.2% were 45 years or older. Females represent 70.7% (P = 0.01), with female-to-male ratio of 4.1:1. Near-total thyroidectomy was done in 70.7% of the cases where papillary cancer was found in 80.8% and node metastasis in 10.5%. Radioactive I (RA I) was given an all cases (dose range, 80-150 mCi) with ablation success rate of 79.2%. Locoregional recurrence and metastasis (lungs and bones) were found in 2% and 6.8%, respectively. Multivariate Cox regression analysis showed that the mean ablation dose of RA I (odds ratio, 1.045; 95% confidence interval, 0.936-1.1189; P = 0.01) and presence of remote deposits (odds ratio, 1.049; 95% confidence interval, 0.836-1.1189; P = 0.01) are the significant influential factor in ablation success rate and survival, respectively.Our data suggest that proper ablation dose of RA I and absence of remote metastasis are the powerful predictors for excellent outcome in WDTC patients.
SP0019 The German Action Plan for Young People with RMDs
Authors: B. Teutriene
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Nowadays there exist numerous self-help groups and organizations. All kinds of groups, clinics, institutions etc publicize their offerings and articulate their interests and demands. <h3>Objectives</h3> Organizations for people with rheumatic diseases have to develop strategies and appropriate measures for their campaigning. In order to lobby successfully, it is important to reach out to decision-makers and media on all levels. <h3>Methods</h3> The German Action Plan for young people with arthritis outlines problems of young people living with RMDs and lists deficits of care with concrete suggestions how they could be improved. Young people with arthritis as well as experts from the Deutsche Rheuma-Liga and pediatric rheumatologists have been involved in the development of the action plan from the beginning. <h3>Results</h3> The German Action Plan is a good basis for the next few years. The release was part of a parliamentary evening in Berlin, where it was handed over to the German Federal Commissioner for the Disabled, Hubert Hüppe, and other members of parliament. Further, it was sent to all the organizations mentioned and presented by our President, Prof. Gromnica-Ihle, on the Standing Conference of the Ministers of Education and Cultural Affairs” (KmK). Talks about ways to improve the situation for children and young people with arthritis have been held on the basis of the action plan with some of the big health insurance companies and the National Association of Physicians in Statutory Health Insurance. By this the German Action Plan is very well respected and recognized. <h3>Conclusions</h3> The German Action Plan is a unique way of summarizing the needs and obstacles of young people with arthritis. It provides clearly defined realistic and necessary requirements for the responsible institutions. <h3>References</h3> The German Action Plan for young people with RMDs <h3>Disclosure of Interest</h3> None Declared
PWE-196 Prevalence of Obesity, by Specialty, amongst Inpatients in the South of England
Authors: T Ambrose, S Cullen, G Baker, M Smith, M Elia, R Leach, A De Silva
Journal: Gut (2013)

<h3>Introduction</h3> Rates of obesity, defined by Body Mass Index (BMI) ≥30kg/m<sup>2</sup>, are rising in the United Kingdom. The prevalence, by specialty, of obesity amongst inpatients has not been well studied. <h3>Methods</h3> A multicentre, hospital-wide audit across three Trusts in the South of England was performed on a single day to ascertain the prevalence of obese inpatients by specialty. Patients were classified according to specialty (medical, surgical, orthopaedic, intensive care) and allocated a BMI category based on National Institute for Clinical Excellence guidelines (1). <h3>Results</h3> 1163 patients were audited (575 male). 778 were medical patients, 222 surgical, 130 orthopaedic, and 33 intensive care. Mean age was 69.3 years with a significant mean age difference between specialties (medical 71.4, surgical 67.7, orthopaedic 61.9, intensive care 60.4) and independent of the hospital studied. 260 patients (22%) had a BMI≥30kg/m<sup>2</sup>, of which 103 (9%) had a BMI≥35kg/m<sup>2</sup>. A significant difference in this latter group was observed between specialties (orthopaedic 18%, intensive care 9%, surgical 9%, medical 7% (p &lt; 0.001)). No effect of gender was observed but there was an independent effect of increasing age and higher BMI. <h3>Conclusion</h3> Approximately one quarter of inpatients in our multicentre audit were obese according to BMI criteria with 9% significantly obese (BMI≥35kg/m2). Rates of obesity are similar to rates of malnutrition in hospitals. Higher BMI were observed in orthopaedic and intensive care specialties than in medical and surgical. Doctors, nurses and managers should be aware of this variation for training and resource allocation purposes. <h3>Disclosure of Interest</h3> None Declared. <h3>Reference</h3> Obesity: the prevention, identification, assessment and management of overweight and obesity in adults and children. National Institute for Health and Clinical Excellence. December 2006.
Abstract 3128: mTOR expression and activity patterns in gastroenteropancreatic neuroendocrine tumors
Authors: Atsuko Kasajima, Marianne Pavel, Silvia Darb-Esfahani, Aurelia Noske, Albrecht Stenzinger, Hironobu Sasano, Manfred Dietel, Carsten Denkert, Christoph Röcken, Bertram Wiedenmann, Wilko Weichert
Journal: Cancer Research (2010)

Abstract Recently, novel small molecules targeting the mammalian target of rapamycin (mTOR) have been successfully tested for the treatment of endocrine neoplasias. Since these drugs will certainly be used as routine therapeutics in the near future, it is surprising that information on the exact expression patterns of mTOR and its downstream target 4EBP1 in endocrine tumors is still lacking. We investigated expression of mTOR and total as well as phosphorylated 4EBP4 in specimen of endocrine tumors by immunohistochemistry and correlated our findings with clinicopathologic variables and patient prognosis. We found that 61 (61.6%), 92 (92.2%), 79 (79.8%) and 69 (69.7%) out of 99 neuroendocrine foregut and midgut tumors were positive for mTOR, 4EBP1, cytoplasmic phospho-4EBP1 (p-4EBP1) and nuclear phospho-4EBP1, respectively. mTOR, 4EBP1 and p-4EBP1 (either cytoplasmic or nuclear) expression was higher in foregut tumors than in midgut tumors. Expression of mTOR was higher in foregut tumors with distant metastases (p=0.035) when compared to their locally restricted counterparts. 4EBP1 as well as p-4EBP1 (either cytoplasmic or nuclear) expression was associated with higher Ki-67 positivity and thereby proliferative activity. mTOR expression and activity as measured by phosphorylation of its downstream target 4EBP1 vary considerably in dependence of tumor location and metastatic status. We hypothesize that differences in mTOR expression patterns and/or activity might predict response to mTOR inhibitors which should be taken into account when future clinical trials with these substances are being planned. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. 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 3128.
IMPROVING OUTCOMES OF PATIENTS PRESENTING WITH ANTERIOR ST ELEVATION MYOCARDIAL INFARCTION WHO UNDERGO PRIMARY PERCUTANEOUS PRIMARY INTERVENTION OVER 20 YEARS IN A TERTIARY CENTER
Authors: Amgad G. Mentias, Amr F. Barakat, Mohammad Raza, Russell Raymond, Venu Menon, Conrad Simpfendorfer, Irving Franco, Stephen Ellis, E. Murat Tuzcu, Samir Kapadia
Journal: Journal of the American College of Cardiology (2016)
AB1188-HPR Enhancing Patient Awareness of Symptoms May Lead to Poorer Outcomes after One Year– Results from A Randomized Controlled Trial: Table 1.
Authors: R.H. Moe, M. Grotle, I. Kjeken, I.C. Olsen, P. Mowinckel, E.A. Haavardsholm, K.B. Hagen, T.K. Kvien, T. Uhlig
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Patient education is recommended as a core treatment for hand, hip and knee osteoarthritis (OA), but little is known about the effects of the various modes of delivery. <h3>Objectives</h3> To examine the effects of an integrated outpatient OA clinic, including a brief, multidisciplinary educational programme for patients with hand, hip, knee, or generalized OA, compared to usual care, assessed 12 months later. <h3>Methods</h3> Patients referred to a rheumatology clinic with a clinical OA diagnosis were randomized to either usual individual care, or integrated care combined with a 3.5h multidisciplinary educational programme that included group interaction with discussions of symptoms and disease consequences. Outcomes included pain, fatigue, stiffness on numeric rating scales (NRS), and disease specific functioning reported on Australian/Canadian Hand Osteoarthritis Index (AUSCAN) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Group differences were examined by mixed model analyses with random intercept, adjusted for baseline values. <h3>Results</h3> Of 390 patients, 86.4% (n=337) were women, and mean age was 63.1 (SD 8.0) years. At 12 months the integrated care group reported more pain and fatigue compared to the usual care group (Table). No other significant differences were found. <h3>Conclusions</h3> A brief, multidisciplinary educational programme may have increased awareness of symptoms, possibly resulting in poorer outcomes on hand pain and fatigue compared to usual care after one year. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.5763