tbuckley/cabot-search huggingface dataset:
Abstract 3384: Depletion of NEDD9 destabilizes Aurora A kinase and augments efficacy of inhibitors.
Authors: Ryan J. Ice, Sarah McLaughlin, Mark Culp, Erik Eddy, Ryan Livengood, Elena Pugacheva
Journal: Cancer Research (2013)

Abstract Aurora A Kinase (AURKA) is overexpressed in 96% of human cancers and is considered an independent marker of poor prognosis. While the majority of tumors have elevated levels of AURKA protein, only few have AURKA gene amplification; therefore, posttranscriptional mechanism regulating AURKA protein levels are significant. In this study, we show that the known activator and binding partner of AURKA, NEDD9, is directly involved in AURKA stability. Analysis of comprehensive breast cancer tissue microarray revealed a tight correlation between expression of both proteins and significantly increased prognostic value. A decrease in AURKA proteins, concomitant with increased ubiquitination and proteasome-dependent degradation, occurs due to depletion or knockout of NEDD9 proteins. Re-expression of wild type (WT) NEDD9 was sufficient to rescue the observed phenomenon. Binding of NEDD9 to AURKA is critical for AURKA stabilization. Mutation of S296E was sufficient to disrupt the binding and reduce the level of AURKA protein. Mechanistically, NEDD9 stabilizes AURKA by limiting the binding of cdh1-substrate recognition subunit of APC/C Ubiquitin Ligase to AURKA. Moreover, depletion of NEDD9 in tumor cells increased their sensitivity to AURKA inhibitors. Combinational therapy using NEDD9 shRNAs and AURKA inhibitors had a profound inhibitory effect on tumor initiation and later, metastasis in lungs of human tumor xenografts. Our findings provide evidence for successful application of AURKA inhibitors for treatment of solid tumors, which often overexpress NEDD9. Citation Format: Ryan J. Ice, Sarah McLaughlin, Mark Culp, Erik Eddy, Ryan Livengood, Elena Pugacheva. Depletion of NEDD9 destabilizes Aurora A kinase and augments efficacy of inhibitors. [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 3384. doi:10.1158/1538-7445.AM2013-3384
CB-01 * TARGETING COLLAGEN REGULATION IN GLIOBLASTOMA MULTIFORME
Authors: F. Abaitua, T. Crook, K. O'Neill, N. Syed
Journal: Neuro-Oncology (2014)

Extracellular matrices (ECM) are quintessential complex structures that provide cells and tissues of functional support for cell adhesion and migration, cell-to-cell communication and differentiation. Collagens are fibrillar proteins that constitute the major component of ECM and have key structural roles. Intracellular maturation of collagen precursors, prior to secretion, is dependent on the hydroxylation of collagen proline residues. This reaction is mediated by collagen prolyl 4-hydroxylases (P3H and P4H families' enzymes) in the presence of α-ketoglutarate, oxygen, Fe2+ and ascorbate. It is already known that ECM and collagen prolyl-hydroxylases are important players in cancer migration and invasion, but little has been explored in brain tumours and hypoxia. We have focused our investigations on glioblastoma multiforme (GBM) using two independent and specific inhibitors of collagen prolyl-hydroxylases: Ethyl 3,4-dihydroxybenzoate (EDHB), an α-ketoglutarate competitor, and 3,4-Dehydro-DL-proline (L-Proline analogue). The presence of these inhibitors showed a dramatic reduction in cell proliferation in a panel of established GBM cell lines. Similar results were obtained in primary cell lines from GBM tumours and melanoma brain metastasis. The mechanisms behind these effects are independent of apoptosis and we are currently exploring the role of autophagy and cell cycle arrest as possible other mechanisms. Surprisingly, even in low oxygen concentration (1%) there was a significant reduction in proliferation. Collagen regulation and its role in cell proliferation in both normoxic and hypoxic conditions will be discussed as a potential new therapeutic strategy for GBMs.
A Trial of Etanercept, a Recombinant Tumor Necrosis Factor Receptor:Fc Fusion Protein, in Patients with Rheumatoid Arthritis Receiving Methotrexate
Authors: Michael E. Weinblatt, Joel M. Kremer, Arthur D. Bankhurst, Ken J. Bulpitt, Roy M. Fleischmann, Robert I. Fox, Christopher G. Jackson, Mary Lange, Daniel J. Burge
Journal: New England Journal of Medicine (1999)

Patients treated with methotrexate for rheumatoid arthritis often improve but continue to have active disease. This study was undertaken to determine whether the addition of etanercept, a soluble tumor necrosis factor receptor (p75):Fc fusion protein (TNFR:Fc), to methotrexate therapy would provide additional benefit to patients who had persistent rheumatoid arthritis despite receiving methotrexate.
Abstract 1297: Engrailed-2 (EN2) represses the transcription of the CST6 tumour suppressor gene in prostate cancer
Authors: Richard Morgan, Guy Simpson, Agnieszka Michael, Hardev S. Pandha
Journal: Cancer Research (2012)

Abstract Engrailed-2 (EN2) is a homeodomain-containing transcription factor that is expressed in prostate and breast tumours but not in normal adult tissue. Although EN2 protein is known to be secreted by prostate tumours and is a potential urine based biomarker of this disease, its function in prostate tumours is unknown. In this study we have used siRNA-mediated knock down of EN2 as well as forced over expression in prostate cancer cells. Although neither treatment has a significant effect on cell survival, we identify two key transcriptional targets of EN2, the tumour suppressor gene CST6 and the Death Receptor ligand TRAIL, the transcription of which are repressed and activated by EN2, respectively. EN2 synergises with epigenetic changes to silence CST6, and may function to block CST6 expression very early in the development of malignancy. Further, we show that EN2 protein can regulate gene transcription in non-malignant prostate cells when supplied externally, indicating that EN2 secretion by prostate tumour cells may be able to modify its microenvironment. 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 1297. doi:1538-7445.AM2012-1297
Abstract 98: The biological significance of T3-regulated endoglin in human hepatoma cells.
Authors: Yang-Hsiang Lin, Ya-Hui Huang, I-Hsiao Chung, Kwang-Huei Lin
Journal: Cancer Research (2013)

Abstract Hypothyroidism has been associated with significantly elevated risk for hepatocellular carcinoma (HCC), although the precise underlying mechanisms remain unknown at present. Thyroid hormone (T3) and its receptor (TR) are involved in metabolism and growth. Endoglin is a T3/TR candidate target gene identified from our previous studies. Here, we demonstrated that T3 positively regulates endoglin mRNA and protein levels, both in vitro and in vivo. The thyroid hormone response elements (TRE) of endoglin were identified at positions -2114/-2004 and -2032/-1973 of the promoter region using the electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay. Endoglin was downregulated in subgroups of HCC patients, and significantly associated with histology grade (negative association, p = 0.001), and this expression level was significantly associated with TRα1 in these HCC patients. Knockdown of endoglin expression in HCC cells promoted cell proliferation in the presence of T3. Moreover, endoglin stabilized p21 expression at the translational level. Based on the collective findings, we propose that endoglin is stimulated by T3 to stabilize p21, leading to the inhibition of cell proliferation. Endoglin and TRα1 levels are reduced in HCC, resulting in increased proliferative activity. Citation Format: Yang-Hsiang Lin, Ya-Hui Huang, I-Hsiao Chung, Kwang-Huei Lin. The biological significance of T3-regulated endoglin in human hepatoma cells. [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 98. doi:10.1158/1538-7445.AM2013-98
A phase I randomized trial to assess the effect on skin infiltrate thickness and tolerability of topical phosphodiesterase inhibitors in the treatment of psoriasis vulgaris using a modified psoriasis plaque test
Authors: S.D. Snape, W. Wigger-Alberti, U.M. Goehring
Journal: British Journal of Dermatology (2016)

Oral phosphodiesterase (PDE)4 inhibitors have shown efficacy in chronic obstructive pulmonary disease and psoriasis. To assess the effectiveness, local safety and tolerability, and systemic pharmacokinetics of two topical PDE4 inhibitors, roflumilast and TAK‐084, in plaque psoriasis. An intraindividual comparison of six topical products was made in 15 patients aged 18–65 years with stable chronic plaque psoriasis in an investigator‐blinded, within‐subject randomized study. The products evaluated were calcipotriol 0·005% cream; betamethasone valerate 0·1% (both in their marketed formulations); investigational cream formulations of roflumilast 0·5% and TAK‐084 0·5% and 5%; and a vehicle cream formulation as a control. Each treatment was applied daily to different test sites located on psoriasis plaques for 3 weeks. The primary end point of (mean) change from baseline in skin infiltrate thickness after 3 weeks of treatment showed statistically significant improvements for all treatments: betamethasone valerate cream (−286·9 μm), the selective PDE4 inhibitors roflumilast 0·5% (−237·1 μm) and TAK‐084 (0·5% cream, −153·6 μm; 5% cream, −216·7 μm) and calcipotriol 0·005% (−187·7 μm) when compared with vehicle cream control (all P < 0·001). Both the TAK‐084 5% and roflumilast 0·5% formulations performed well overall compared with the potent corticosteroid, betamethasone, and were ranked better than the vitamin D analogue calcipotriol. All adverse events were mild or moderate and none was serious. Topical treatment with cream formulations of the PDE4 inhibitors roflumilast and TAK‐084 reduced inflammation, measured as a change in skin infiltrate thickness, and reduced psoriasis severity. Corticosteroid treatments have known systemic and cutaneous side‐effects; PDE4 inhibitors could offer an alternative to these and deserve further study.
Treatment of Crohn's Disease with 6-Mercaptopurine
Authors: Daniel H. Present, Burton I. Korelitz, Nathaniel Wisch, Joseph L. Glass, David B. Sachar, Bernard S. Pasternack
Journal: New England Journal of Medicine (1980)

To test the effectiveness of 6-mercaptopurine (6-MP) in the treatment of Crohn's disease, we entered 83 chronically ill patients into a two-year double-blind study comparing 6-MP with placebo. Crossover data showed that improvement occurred in 26 of 39 courses of 6-MP (67%) as compared with three of 39 courses of placebo (8%) (P less than 0.001). Non-crossover data likewise confirmed the superiority of 6-MP. The drug was more effective than placebo in closing fistulas (31 vs 6%) and in permitting discontinuation or reduction of steroid dosage (75 vs. 36%) (P less than 0.001). The onset of response to 6-MP was often delayed, with 32% of patients taking longer than three months to respond, and 19% taking longer than four months. Adverse side effects to 6-MP occurred in 10% of patients and were uniformly reversible. We conclude that 6-MP is an effective and useful agent in the management of Crohn's disease.
183 RECURRENCE OF PRIMARY SCLEROSING CHOLANGITIS AFTER LIVER TRANSPLANTATION
Authors: S. Singh, J.A. Talwalkar, W.R. Kim, E.J. Hay, J.J. Poterucha, M.R. Charlton, C.B. Rosen, J.K. Heimbach, R.H. Wiesner
Journal: Journal of Hepatology (2013)
FRI0339 Systematic review of drug trials in the treatment of giant cell arteritis.
Authors: M. Yates, Y. Loke, R. Watts, A. MacGregor
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Giant cell arteritis is the most common vasculitis in individuals aged greater than 50yrs in the western world and has significant morbidity. It is a medical emergency with up to 20% of patients suffering with visual loss. Treatment with high dose glucocorticoids (GC) is the mainstay of treatment. Several other agents have been tried as adjuncts to GC in the treatment of GCA. <h3>Objectives</h3> The objective was to conduct a meta-analysis of these therapies to ascertain their benefit over GC regimens. <h3>Methods</h3> MEDLINE, CENTRAL and EMBASE searches were used to identify randomised control trials and large observational studies on the treatment of GCA with GC. Searches were carried out independently by two researchers (MY and YL) to date 7<sup>th</sup> January 2013. Trials or observational studies were included if more than 20 patients were recruited into each arm of the trial, there was clear criteria for the diagnosis of GCA and did not include patients with exclusively with a diagnosis of PMR. The study was also required to be carried out on humans greater than 55yrs of age and the length of follow-up was at least 6 months. Exclusion criteria consisted of; not reporting of initial dose of GC; or not reporting total cumulative dose; or there were no recorded outcomes of patients. <h3>Results</h3> The combined MEDLINE, CENTRAL and EMBASE searches retrieved 3804 articles. Of these only 36 met primary inclusion criteria. 15 of these studies reported some information about the GC regimen used and were included in the qualitative analysis. Only nine of these were of sufficient quality to be included in the meta-analysis. Together these comprised of 568 participants of which 72% were female and had a mean age of 73years. 84% had a positive temporal artery biopsy. Initial starting steroid dose equivalent to prednisolone ranged from 10mg to 1000mg with duration of therapy ranging 26 to 94 weeks. Forrest plots were constructed to assess for advantage of intervention over control arm with pooled estimates if more than one study was available for a specified adjunct (advantage towards control resulted in a RR &lt;1.0 and advantage to control RR &gt;1.0). Three studies compared various GC regimens, with two comparing IV GCs (RR = 0.78 95% CI = 0.54 to 1.12). Another three used methotrexate as an adjunct agent (RR = 0.85 95% CI = 0.66 to 1.11). The remaining three trials compared prednisolone to dapsone, infliximab and hydroxychloroquine. No GC regimen with an adjunct agent was shown to have consistent advantage over oral GC alone. <h3>Conclusions</h3> The results from this meta-analysis show that there is no benefit from adjunct agents in terms of efficacy or toxicity. Given the relatively large differences seen in the trials with regard to rate of withdrawal and study duration of GCs, has a bearing on relapse rate. Studies of appropriate power and duration are needed to answer these questions. <b>Disclosure of Interest</b>: None Declared
AB1022 Involvement of Wrist Extensor Tendons and Joints in Rheumatoid Arthritis Assessed by Ultrasonography: Table 1
Authors: V. Skakic, A. Skakic
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objectives</h3> Tendinopathy involving the extensor tendons of the wrist is frequent in patients with rheumatoid arthritis (RA) and is common reason of pain in wrist interfering with wrist joints synovitis. Aim of study was to assess, by ultrasonography (US), the frequency of extensor tendon involvement in the wrist joint of patients RA and analyze their relatioship with synovitis of radiocarpal (RC) and intercarpal (IC) joints <h3>Methods</h3> Fifty consecutive RA patients (36 female, mean age 48) with bilateral wrist pain were included in the study. The extensor tendons (ET) were scanned bilaterally of the all 6 compartments on the dorsal aspect of the wrist. The presence of US findings indicative of synovitis of RC and IC joints and also ET tenosynovitis was investigated using grey-scale (GS) and power Doppler (PD) US scoring (semi-quantitative range 0-2 for both). <h3>Results</h3> Synovitis of RC and IC joints was found in 29 (58%) and 27 (54%) respectively, of 50 RA patients. Analysing 100 wrists we found RC synovitis GS/PD in 58/49 (grade 1 49/45; grade 2 9/4) of patients respectively. We also found IC synovitis GS/PD in 51/48 (grade 1 47/44; grade 2 4/4) of patients respectively. Tenosynovitis of all six extensor compartements was found 9 (18%) of 50 patients.The most frequently involved were the extensor carpi ulnaris (ECU) and extensor digitorum communis tendons (EDC). Analysing all 100 wrists we found ECU tenosynovitis in 21/17 (grade 1 19/15; grade 2 2/2) of patients respectively. We also found EDC tenosynovitis in 12/12 (grade 1 10/12; grade 2 2/0) of patients respectively (Table 1). Presence of ECU and EDC tenosynovitis correlated with synovitis of both RC and IC joints: Among all 21 ECU, 18 (86%) were in wrists with RC synovitis and 16 (76%) in wrists with IC synovitis and among all 12 EDC, 10 (83%) were in wrists with RC synovitis and 9 (75%) in wrists with IC synovitis. However, 3 (14%) of ECU and 2 (17%) of EDC were found in wrists with no observations of RC or IC synovitis. <h3>Conclusions</h3> The present study provides evidence of the ability of US to reveal a relatively high frequency of extensor tendon involvement at the wrist level in RA patients associated with involvement of the wrist joint. These data recommend US as a useful examination tool in daily clinical assessment of tendons and joints in RA. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.2654
Abstract 1589: Isorhamnetin suppresses skin cancer through direct inhibition of MEK1 and PI3-K
Authors: Jong-Eun Kim, Dong-Eun Lee, Ki Won, Joe Eun Son, Sang Kwon Seo, Jixia Li, Sung Keun Kung, Yong-Seok Heo, Madhusoodanan Mottamal, Ann M. Bode, Zigang Dong, Hyong Joo Lee
Journal: Cancer Research (2012)

Abstract Isorhamnetin is a plant flavonoid that is found in fruits and medicinal herbs and exerts anticancer effects. However, the underlying molecular mechanism of the chemopreventive potential of isorhamnetin remains unknown. Here, we report anti-skin cancer effects of isorhamnetin. In an in vivo mouse xenograft model injected with A431 human skin epithelial carcinoma cells, isorhamnetin reduced tumor growth and COX-2 expression. Isorhamnetin inhibited epidermal growth factor (EGF)-induced neoplastic cell transformation of JB6 mouse epidermis cells and anchorage-dependent and -independent growth of A431 cells. Isorhamnetin attenuated EGF-induced cyclooxygenase (COX)-2 expression in JB6 cells and A431 cells. The EGF-induced phosphorylation of extracellular signal-regulated kinases, p90 and p70 ribosomal S6 kinases, and Akt was suppressed by isorhamnetin. In vitro and ex vivo kinase assay data demonstrated that isorhamnetin inhibited the kinase activity of MEK1 and PI3-K and the inhibition was due to direct binding with isorhamnetin. Notably, isorhamnetin bound directly to MEK1 in an ATP-noncompetitive manner and to PI3-K in an ATP-competitive manner. Overall, these results indicate that isorhamnetin has potent anti-cancer activity and it primarily targets MEK and PI3-K, which might contribute to the chemopreventive potential of certain foods. 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 1589. doi:1538-7445.AM2012-1589
A4.09 Adipokines affect differentiation of osteoarthritis and osteoporosis spongiosa-derivedmesenchymal stromal cells
Authors: L Tsiklauri, J Werner, KW Frommer, U Müller-Ladner, S Wenisch, E Neumann
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Introduction</h3> Age-related bone loss and articular cartilage destruction are accompanied by increased bone marrow fat infiltration. Bone marrow adipocytes have high secretory activity including secretion of proinflammatory (eg, adipokines) and matrix-degrading (eg, matrix metalloproteinases, MMPs) proteins and may be involved in progressive bone loss observed in osteoarthritis and osteoporosis. These adipocyte-derived factors most likely influence differentiation of bone marrow-derived mesenchymal stem cells (MSCs) into osteoblasts and adipocytes. Therefore, we analysed the effects of resistin, leptin and visfatin on MSC differentiation and their distribution in bone. <h3>Methods</h3> Spongiosa containing bone marrow from femoral heads of patients undergoing hip replacement after osteoporotic femoral neck fracture or osteoarthritis were collected. Primary spongiosa-derived mesenchymal stromal cells (hMSCs) as well as commercially obtained MSCs were cultured in adipogenic and osteogenic media 3 weeks with/without adipokines. mRNA expression of adipokines, bone marker genes, TIMPs and MMPs of stimulated hMSCs/MSCs and of bone samples were evaluated by real time PCR. <h3>Results</h3> Exression of visfatin was significantly increased in osteoporotic bone (n = 10)&nbsp;compared to non-osteoporotic bone (n = 11). Higher expression of leptin was also visible in osteoporotic bone. MSC&nbsp;stimulation with visfatin significantly increased MMP13 expression (eg, d21:72-fold) during adipogenic differentiation but not leptin and resistin. During osteogenic differentiation MMP2 was reduced. In contrast to adipogenic differentiation, viafatin led to reduced MMP13&nbsp;expression (eg, d21:55-fold) in osteogenic differentiated cells (n = 2). Mainly visfatin decreased TIMP1&nbsp;(eg, d21: 2.86-fold), TIMP2&nbsp;(eg, d21: 3.17-fold), and RunX2&nbsp;(eg, d21:5.85-fold)&nbsp;production, whereas leptin and resistin showed no effect. <h3>Conclusion</h3> Visfatin and leptin levels were increased in osteoporotic bone tissue. Visfatin induced MMP13 expression in adipogenic cells while the production of MMP2 and MMP13 was reduced during osteogenic differentiation. The altered MMP production mediated by visfatin might influence bone remodelling at the adipose tissue/bone interface. Moreover, high levels of leptin in the osteoporotic bone might promote bone degradation. Although leptin had no local effect on MSCs differentiation <i>in vitro</i>, it may promote bone degradation by affecting other cell types.
Prediction of BCNU Pulmonary Toxicity in Patients with Malignant Gliomas
Authors: Patricia A. Aronin, M. S. Mahaley, Seth A. Rudnick, Lynn Dudka, James F. Donohue, Robert G. Selker, Pearl Moore
Journal: New England Journal of Medicine (1980)

Symptomatic pulmonary disease occurred in 20 per cent of 93 patients with anaplastic gliomas being treated with carmustine (BCNU). An analysis of the variables has revealed a relation between the occurrence of pulmonary toxicity on the one hand, and the total cumulative dose of BCNU, the number of cycles over which the BCNU was administered, the history of lung disease, the patient's age, and the platelet-count nadir after the first course of BCNU on the other. An equation has been generated that allows prediction of pulmonary toxicity during the course of therapy with BCNU with 80 per cent accuracy. Pretreatment analysis of individual cases should allow safe use of BCNU and prevention of most of the serious pulmonary complications caused by this drug. (N Engl J Med. 1980; 303:183–8.)