tbuckley/cabot-search huggingface dataset:
PTU-123 Factors that Anticipate Clinical/Therapeutic Outcomes to Prucalopride
Authors: A D Farmer, P Harvey, D Haldar, N Quraishi, Q Aziz
Journal: Gut (2013)

<h3>Introduction</h3> Chronic constipation (CC) is a prevalent disorder that has a significant negative impact on quality of life. Traditional management has focused on lifestyle measures and laxative. Prucalopride, a selective high affinity 5-HT<sub>4</sub> receptor agonist, has been demonstrated to an effective treatment of severe CC. However, its efficacy in secondary care and factors that predict clinical response are incompletely understood. Our aim was thus to identify baseline factors that may predict positive clinical outcomes in patients taking prucalopride for CC. <h3>Methods</h3> A single centre, prospective open label trial was undertaken in patients with primary and secondary CC, defined as less than 2 spontaneous complete bowel movements (SCBM) per week, who were commenced on prucalopride. Validated questionnaires were used to assess the severity of symptoms (patient assessment of constipation symptoms (PAC-SYM)), somatic symptoms (patient health questionnaire (PHQ-12-SS)) and the personality trait of neuroticism (big five inventory-neuroticism scale (BFI-N)). At follow up, clinical response was defined as the proportion of patients achieving 3 or more SCBM per week. <h3>Results</h3> 64 patients (59 female, mean age 48.3 years, range 19–83) had a mean SCBM per week of 1.6 (range 0.5–2). At a mean follow up of 4.6 weeks (range 4–8) 40/64 (62.5%) patients achieved clinical response. 8/64 (12.5%) did not tolerate treatment due to side effects. In an intention to treat analysis, mean SCBM per week increased from 1.6 to 3.2 (<i>p</i> = 0.01) with mean PAC-SYM scores reducing from 27.7 to 20 (<i>p</i> = 0.001). Logistic regression analysis demonstrated that BFI-N (odds ratio 8.7, 95% confidence interval (CI), 1.99–64, <i>p</i> &lt; 0.01) and slow transit constipation (STC) (odds ratio 1.4, 95% CI, 1.20–2.1, <i>p</i> &lt; 0.01) were independently associated with positive treatment outcomes. <h3>Conclusion</h3> Prucalopride is a useful, generally well tolerated, treatment for the management of CC in secondary care. These data suggest that efficacy could be enhanced by targeting patients with STC and in those who are more neurotic. Further work is now warranted to confirm these findings in a larger cohort of patients. <h3>Disclosure of Interest</h3> A. Farmer Paid Instructor for: Shire Pharmaceuticals, P. Harvey: None Declared, D. Haldar: None Declared, N. Quraishi: None Declared, Q. Aziz: None Declared
AB0229 Generalized long term bone loss in early rheumatoid arthritis in the biologic treatment era – a ten year observational study
Authors: A. Prøven, K. Helgetveit, G. Haugeberg
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Osteoporosis is a well known extra-articular manifestation of the inflammatory disease process in rheumatoid arthritis (RA), causing increased fracture risk. Potent anti-inflammatory treatment blocking e.g. TNF-alpha has been shown to reduce the rate of generalized bone loss [1]. Several short term studies have illuminated our understanding on bone loss in RA; however in general there is a lack of long term follow-up studies exploring bone density changes in a long term perspective. <h3>Objectives</h3> To study long term changes in bone density at hip and spine in patients with early RA in the biologic treatment era. <h3>Methods</h3> Between 1999 and 2001 a total of 93 RA patients fulfilling the ACR RA criteria (disease duration &lt; 1 yr) were prospectively included in a long term observational study. According to protocol a broad specter of demographic and clinical data was collected. Bone mineral density (BMD) measurements at lumbar spine and hip (femoral neck and total hip) were performed by trained nurses using the same dual energy x-ray absorptiometry (DXA) equipment Lunar Prodigy (General Electric) at baseline and after 2, 5 and 10 yrs. The machine was stable during the whole period. <h3>Results</h3> Patient characteristics at baseline: mean (SD) age 50.4 (13.6) yrs, females 61.7%, RF+ 62.8%, CCP+ 60.6% and erosive 2.1%. Baseline disease characteristics: swollen-28 joints 8.4, tender-28 joints 9.7, MHAQ 0.68, ESR 29.2 mm/hr and CRP 28.9 mg/dl. Ever use of prednisolone 73.4%, synthetic DMARDs 93.6% and biologic DMARDs 53.2%. Rate of bone loss at 2, 5 and 10 years is shown in the table. At femoral neck and total hip bone loss was linear with average annual bone loss of 0.64% at femoral neck and 0.49% at total hip. <h3>Conclusions</h3> Our data suggest that aggressive anti inflammatory treatment protects against bone loss at spine whereas bone loss continues at the hip. However interestingly the rate of bone loss observed in our study at hip and spine is at the same rate as reported in the general population [2, 3]. <h3>References</h3> Haugeberg G et al. ARD 2009;68:1898-901. Melton LJ et al. Osteoporos Int 2000;11:592-9. Warming L et al. Osteoporos Int 2002;13:105-12. <h3>Disclosure of Interest</h3> None Declared
Comparison of Endoscopic Ligation and Propranolol for the Primary Prevention of Variceal Bleeding
Authors: Shiv K. Sarin, Gurwant S. Lamba, Mandhir Kumar, Alok Misra, Nandagudi S. Murthy
Journal: New England Journal of Medicine (1999)

We compared propranolol therapy and endoscopic ligation for the primary prevention of bleeding from esophageal varices. This prospective, controlled trial included consecutive eligible patients who had large varices (>5 mm in diameter) that were at high risk for bleeding. The patients were assigned to either propranolol therapy, at a dose sufficient to decrease the base-line heart rate by 25 percent, or variceal ligation, to be performed weekly until the varices were obliterated or so reduced in size that it was not possible to continue treatment.
Abstract 880: Inhibition of MMP14 potentiates the antiglioma effect of TMZ and ionizing radiation
Authors: Ilya Ulasov, Brenda Auffinger, Bart Thaçi, Peter Pytel, Natalya Kaverina, Feifei Liu, Atique Ahmed, Maciej Lesniak
Journal: Cancer Research (2012)

Introduction. Glioblastoma multiforme (GBM) is the most common primary central nervous system tumor in adults. The median survival after surgical intervention alone is approximately 6 months and the addition of radiation and chemotherapy (like Temozolomide, TMZ) can only extend this up to 14.6 months. Other treatment options are therefore needed for better disease management and improved survival. We ran an Affymetrix analysis on the Rembrandt Database to determine the role of metalloproteinase expression in the biology of GBMs. High expression of MT1-MMP (MMP14) correlated with a poor patient survival. MMP14, as other metalloproteinases, is a cellular based proteolytic endopeptidase that plays a role in extracellular matrix (ECM) and basic membrane (BM) degradation. In glioma, expression of MMP14 is correlated with tumor invasiveness and associated with the CD133+ phenotype. Inhibition of MMP14 could therefore offer a potential target for the therapy of GBM. Experimental methods. Expression of MMP14 was determined in 100 primary and recurrent gliomas by immunohistochemistry. We performed quantitative RT-PCR and Western blotting analysis of MMP14 expression to investigate the effect of radiation and TMZ on U87 and U251 glioma cells. We used the Ingenuity Software to analyze the relationship between MMP14 and proteins responsible for angiogenesis and cell proliferation. Anti-angiogenic effect of MMP14 knockdown was determined by tube formation assay and angiogenic cytokine array (RayBio). Finally, treatment of MMP14 knockdown of glioma cells with temozolomide and ionizing radiation was analyzed by MTT assay. Results. Genetic silencing of MMP14 leads to inhibition of glioma cell proliferation and cell cycle arrest. We also show that silencing of MMP14 results in downregulation of angiogenic markers at the mRNA and protein level. Furthermore, we have found that inhibition of MMP14 expression in glioma cells improves the therapeutic effect of temozolomide and ionizing radiation. Conclusions. This study suggests that silencing of MMP14 via RNAi technology improves therapeutic effect of TMZ and ionizing radiation on glioma cell proliferation. Therefore, inhibition of MMP14 provides a new target for treatment of gliomas.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 880. doi:1538-7445.AM2012-880
Abstract 3714: Characterization of a selective focal adhesion kinase (FAK) inhibitor in a panel of glioblastoma cell lines identify rational drug-drug combination strategies
Authors: Shujuan Chen, Natalie Johnson, Kurt R. Auger, Yonghong Xiao, Haoqiang Ying, Joseph Marszalek, Richard Middleton, Jannik N. Andersen, John P. McGrath, Lynda Chin
Journal: Cancer Research (2012)

Abstract Focal Adhesion Kinase (FAK) is a key regulator of cancer cell migration and invasion and overexpression of FAK and Src has been associated with resistance to current anticancer therapies. Thus, inhibition of FAK may represent a promising therapeutic approach to anti-cancer treatment. We investigated the anti-cancer activity of the FAK inhibitor (GSK2256098) in a panel of 26 human glioblastoma (GBM) cell lines. GBM is one of the most aggressive and lethal forms of cancer, characterized by exponential growth and diffuse invasiveness. Herein, we report that 8/26 GBM cell lines displayed sensitivity to FAK inhibition in both migration and Matrigel invasion assays. GSK2256098 had minimal effect on 2D cell proliferation. Integrated genomic and proteomic analyses revealed up-regulation of the PI3K and MAPK pathways in the FAK inhibitor-resistant GBM cell lines, suggesting possible drug combination strategies. To test this hypothesis, we assessed the effects of combining GSK2256098 with a PI3K inhibitor and a MEK inhibitor in the FAK inhibitor-resistant GBM cell lines. Our results suggest that multi-agent inhibition of FAK and MEK or PI3K may provide an attractive therapeutic strategy for GBM. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3714. doi:1538-7445.AM2012-3714
THU0274 Ultrasonographic Inflammatory Activity Predicts Relapse in Rheumatoid Arthritis in Remission
Authors: K. Ben Abdelghani, S. Miladi, L. Souabni, S. Kassab, S. Chekili, A. Laatar, L. Zakraoui
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Remission is the current aim of treatment in rheumatoid arthritis (RA). Remission is ideally the absence of detectable disease and absence of structural and functional worsening over the time. Infra-clinical synovitis, detected by ultrasound, may persist in patients with remission leading to further structural damage. <h3>Objectives</h3> The aim of this study was to assess the frequency of relapse after clinical remission and the value of US to predict this relapse. <h3>Methods</h3> A prospective study of 30 patients followed-up for RA in remission was conducted. The remission was defined by a Disease Activity Score 28 joints (DAS28) ≤2,6 for at least 3 months under the same therapy. A B-mode and Power Doppler (PD) US examination was assessed by an experienced rheumatologist blinded to clinical data for 22 joints (wrists, 10 metacarpo-phalangeals, 10 proximal interphalangeals joints). A semi-quantitative scale running from 0 to 3 depending on US activity was attributed for each joint for PD. Patients were clinically controlled 3 to 6 months after performing the US. The variability of DAS28 was noted, it was considered significant if the p value &lt;0,05. <h3>Results</h3> The mean age of the thirty patients was 48 years-old (25 females, 5 males). All of them were in remission according to DAS28 with an average of 2,03 [1,13-2,6]. US examination showed synovial hypertrophy in B-mode in 80% of patients and PD signals in 56,7% of patients. The follow-up control was performed on average after 4 months for 27 patients. The variation of DAS28 from baseline was significant (p&lt;0,005). In fact the DAS28 increased of 0,75 [0,10-3,1] for 20 patients, among them 14 were no longer in remission. The DAS28 remained stable for 2 patients and decreased for 5 others. For patients who have reactivation of RA, the mean US PD scale was 4,4, while it was 1,1 for patients who remained in remission. However, the difference wasn9t significant (p=0,12). <h3>Conclusions</h3> For patients in remission, persistent active synovitis in US is a risk factor for futur reactivation of the disease. PD monitoring in daily practice might lead to reduce disease relapses and structural damages. <h3>Disclosure of Interest</h3> : None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.5242
PTU-149 Cambridge-Miami risk assessment for intestinal transplantation
Authors: C Pither, R Sivaprakasam, H Takahashi, S Nishida, A Butler, J Moon, M D Dawwas, S Gabe, N Jamieson, J Woodward, E Island, A Tzakis, S J Middleton
Journal: Gut (2012)

<h3>Introduction</h3> The Cambridge-Miami (CaMi) preoperative risk assessment score has been previously validated in a small cohort and accurately predicted the survival after intestinal transplantation. We undertook a further validation in a larger cohort of patients. <h3>Methods</h3> Co-morbidity and lost venous access are used as putative preoperative risk factors, each scored 0–3 for severity. Patients (72 adults (M:F, 33:39) received an isolated intesinal graft (27), or a cluster graft including intestine (45). <h3>Results</h3> Mean (SD) survival was 1501 (1444) days. The Kaplan–Meier analysis of survival revealed a significant inverse association between survival and CaMi score [logrank test for trend, p&lt;0.0001]. Patients were grouped into CaMi scores of 0 and 1, 2 and 3, 4 and 5, 6 and above, and HR [95% CIs] for death (compared to group 0+1) was found to increase as the CaMi score increased; 1.945 [0.7622 to 5.816], 5.075 [3.314 to 36.17] and 13.77 [463.3 to 120100] respectively and was significantly greater than group 0+1 at group 4+5 (p&lt;0.0001). <h3>Conclusion</h3> The ability to predict survival from the CaMi score might allow better patient selection, and identify patients for earlier transplantation. <h3>Competing interests</h3> None declared.
AB0157 The diagnostic performance of a candidate multi-biomarker score in early rheumatoid arthritis
Authors: A. Novikov, E. N. Alexandrova, A. N. Gerasimov, D. E. Karateev, E. L. Luchihina, E. L. Nasonov
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> In the early phase of rheumatoid arthritis (RA) the patients do not yet fulfill the criteria for disease<sup>1</sup>. To meet the need for improved diagnostic tests and algorithms, various serum biomarkers are being assessed for the improved diagnosis of RA. However, only rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) have gained wide acceptance<sup>2</sup>. <h3>Objectives</h3> A multi-biomarker score (MB) are powerful emerging tests that have the potential to answer significant clinical diagnostics problems by integrating multiple proteomic markers<sup>3</sup>. The aim of this study was to evaluate the performance of a candidate multi-biomarker score in diagnosis of early RA (MBERA). <h3>Methods</h3> We studied 102 patients (pts) with early RA (with&lt;6 months disease duration) (23 man, 79 woman, median age 51, 41-62years),27 pts with systemic lupus erythematosus (SLE), 15 pts with Sjogren's syndrome, 25 pts with ankylosing spondylitis, 24 pts with osteoarthritis, 20 pts with OVERLAP, 9 pts with gout, 22 pts with psoriatic arthritis, 168 pts with undifferentiated arthritis and 297 healthy individuals. 4 antibodies (IgM RF, IgA RF, anti-CCP, AMCV), 3 inflammation markers (ESR, CRP, calprotectin), markers of bone (sRANKL) and cartilage (COMP) metabolism, 27 cytokines (IL-1β,-1ra,-2,-4,-5,-6,-7,-8,-9,-10,-12,-13,-15, -17, basic FGF, eotaxin, G-CSF, GM-CSF, IFN-γ, IP-10, MCP-1, MIP-1α, MIP-1β, PDGF-BB, RANTES, TNF-α, VEGF) serum concentrationswere measured. Analysis of consistency and confidence as biomarkers of early RA was carried out by multivariate logistic regression. <h3>Results</h3> The MBERA score was calculated based on the concentrations of 6 biomarkers (anti-CCP, CRP, IL-6, IFN-γ, GM-CSF, IP-10). The MDERA demonstrate a superior performance (AUC 0,98; sensitivity 94%; specificity 81%; LR+ 4,9; LR- 0,1) versus RF (AUC 0,8; sensitivity 67%; specificity 79%; LR+ 3,2; LR- 0,4) and anti-CCP (AUC 0,7; sensitivity 59%; specificity 87%; LR+ 4,5; LR- 0,4) to diagnosis early RA. <h3>Conclusions</h3> Diagnostic performance of MBERA is superior versus IgM RF and anti-CCP. After accurate validation, this test could be used in clinical laboratory practice. <h3>References</h3> A. Willemze, R.E.M. Toes, T.W.J. Huizinga, L.A. Trouw. New biomarkers in rheumatoid arthritis. Neth J Med. 2012 Nov;70(9):392-9. P. Taylor, J. Gartemann, J. Hsieh, J. Creeden. A Systematic Review of Serum Biomarkers Anti-Cyclic Citrullinated Peptide and Rheumatoid Factor as Tests for Rheumatoid Arthritis. Autoimmune Diseases Volume 2011, Article ID 815038, doi:10.4061/2011/815038. http://www.cap.org/apps/docs/committees/technology/ivdmia.pdf <h3>Disclosure of Interest</h3> None Declared
Abstract 1102: c-Kit regulates stem-like phenotype and chemoresistance in ovarian cancer cells
Authors: Wing Ka Chau, Alice Sze Tsai Wong
Journal: Cancer Research (2011)

Abstract One emerging concept of the development of drug-resistant tumors involves a pool of self-renewing malignant progenitors. However, the factors and molecular mechanisms that govern this process remain largely elusive. It has been reported that the high malignancy of these cells is associated with a more efficient cytokine network. In this study, we characterized tumor-initiating cells (TIC) from human ovarian cancer cell line as a model. In contrast to non-TIC, TIC had higher colony formation ability in vitro and greater tumorigenicity in vivo, suggesting that TIC enrich cancer stem-like cells. Notably, the c-Kit receptor tyrosine kinase and its ligand stem cell factor were significantly elevated in TIC. The use of c-Kit siRNA or small molecule inhibitor imatinib to inhibit c-Kit expression and kinase activity, respectively, in TIC resulted in diminished cell proliferation and survival and in vivo tumorigenicity, confirming that the effect was c-Kit specific. Furthermore, we showed that while the two front-line chemotherapeutic drugs cisplatin and paclitaxel could eliminate non-TIC, it had no effect on TIC. Combining cisplatin/paclitaxel with c-Kit siRNA or imatinib prevented the growth of both tumor cell populations. These effects were found to be dependent on signaling of phosphatidylinositol 3-kinase/Akt, but not extracellular signal-regulated kinase 1/2. These results reveal an important role for c-Kit in regulation of self-renewal and proliferation of ovarian cancer cells, which could be selectively targeted for improved treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1102. doi:10.1158/1538-7445.AM2011-1102
Abstract 5374: Significance of ADCC for the action of trastuzumab quantified by novel procedures
Authors: Timothy E. Kute, John Stehle, David Ornelles, Natalie Walker, Jim Vaughn
Journal: Cancer Research (2012)

Abstract Background: The killing of Her2 + breast cancer cells by the antibody trastuzumab is an attractive therapy because of its specificity and limited side effects. However, many Her2 + positive patients have innate resistants or will become resistant to this treatment. Although Her2 status can be determined by immunohisochemistry or FISH, still only 30% of patients positive for high Her2 status will respond to trastuzumab alone. Improved methods to predict sensitivity to trastuzumab are greatly needed. Since trastuzumab is believed to work by antibody-dependent cell-mediated cytotoxicity (ADCC), we have developed a novel and reproducible bioassay to measure trastuzumab-dependent ADCC which may be predictive of patient response. Methods: Using both an xCELLigence platform (Roche Applied Science) and a flow cytometry assay (PanToXiLux from OncoImmunin, Inc), we measured the ability of mononuclear cells (MNCs) to kill four different breast cancer cell lines in the presence or absence of trastuzumab. Two cell lines used have resistance to trastuzumab and two cell lines have lower Her-2 expression. The xCELLigence platform measures killing in real time while the flow cytometry assay measures the transfer of granzyme B and upstream caspase activity from mononuclear cells to the tumor cells and the activation of cell death processes. The ability of mononuclear cells to bind tumor cells in the presence and absence of trastuzumab was evaluated by microscopy. Using miltenyi beads and immunofluroescence, we have measured which MNC population is most effective in ADCC activity. MNCs from patients with breast cancer and from individuals without disease were analyzed. Results: These studies provide a simple and reproducible assay for ADCC activity. Effective ADCC killing is directly related to Her2 expression on the tumor target. The degree of killing is directly related to the number of mononuclear cells added in the study when trastuzumab is added. Addition of trastuzumab alone to these cell lines results in little killing. MNCs from non-diseased individuals as well as those obtained from breast cancer patients display a broad range of ADCC killing efficiency per cell. Finally, our results demonstrate that NK cells are the major MNC population of effect killing. Conclusion: The two assays presented here and other specific studies show that trastuzumab can work with the immune system to increase cell killing of Her2 overexpressing cells by ADCC. A correlation between the results of these assays and the clinical response to trastuzumab will be presented. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5374. doi:1538-7445.AM2012-5374