tbuckley/cabot-search huggingface dataset:
THU0133 Results from A Phase 2A, Randomized, Multicenter, Double-Blind, Placebo-Controlled, Parallel-Group Study of Jnj-40346527, an Oral CSF-1R Inhibitor, in Patients with Active Rheumatoid Arthritis despite Disease-Modifying Antirheumatic Drug Therapy
Authors: M.C. Genovese, E. Hsia, S. Belkowski, C. Chien, T. Masterson, R. Thurmond, C. Manthey, D. Yan, T. Ge, A. Greenspan
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> JNJ-40346527, an investigational agent, is a selective inhibitor of the colony stimulating factor-1 receptor (CSF-1R) kinase and acts to inhibit macrophage survival, proliferation and differentiation. Based on current understanding of their mechanisms of action, JNJ-40346527 and traditional DMARDS may have complementary effects in reducing inflammation in rheumatoid arthritis (RA). <h3>Objectives</h3> To assess the safety, tolerability, and efficacy of JNJ-40346527 compared with placebo (PBO) administered for 12wks to patients with active RA despite DMARD therapy. <h3>Methods</h3> In this randomized, double-blind, PBO-controlled, parallel-group study, adult RA patients were randomized (2:1) to receive JNJ-40346527 100mg or PBO twice daily. RA patients had active disease (persistent disease activity with ≥6 swollen/6 tender joints at screening and baseline and a CRP level ≥0.8mg/dL at screening) despite MTX, SSZ, and/or HCQ therapy at the time of screening. Patients had to be on MTX, SSZ, and/or HCQ therapy for ≥6 months prior to screening, with a stable dose for minimum of 8wks prior to screening; patients were to continue stable DMARD therapy through wk12. Primary endpoint was change from baseline in DAS28 (CRP) at wk12. Efficacy analyses were based on m-ITT, defined as all randomized patients who had received ≥1 study agent administration and who had a baseline and at least one post-baseline value. Pharmacokinetics (PK) and pharmacodynamics assessments were performed. <h3>Conclusions</h3> Despite evidence of adequate PK exposure and effective peripheral target engagement, no consistent evidence of efficacy was observed in the JNJ-40346527 group vs PBO in patients with active RA despite DMARD therapy. No statistically significant difference was observed between the groups in any of the efficacy parameters analyzed; treatment was generally well-tolerated. <h3>Disclosure of Interest</h3> : M. Genovese Grant/research support: Janssen Research &amp; Development, LLC, E. Hsia Employee of: Janssen Research &amp; Development, LLC, S. Belkowski Employee of: Janssen Research &amp; Development, LLC, C. Chien Employee of: Janssen Research &amp; Development, LLC, T. Masterson Employee of: Janssen Research &amp; Development, LLC, R. Thurmond Employee of: Janssen Research &amp; Development, LLC, C. Manthey Employee of: Janssen Research &amp; Development, LLC, D. Yan Employee of: Janssen Research &amp; Development, LLC, T. Ge Employee of: Janssen Research &amp; Development, LLC, A. Greenspan Employee of: Janssen Research &amp; Development, LLC <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.2404
Abstract 1616: The OPCML tumor suppressor negatively regulates a specific repertoire of 5 receptor tyrosine kinases via a novel proteasomal mechanism, and its recombinant derivative is a potent in-vivo anticancer protein therapy
Authors: Arthur B. McKie, Sebastian Vaughan, Imoh Okon, Joshua L.C. Wong, Elisa Zanini, Eric W-F Lam, Naomi E. Chayen, Hani Gabra
Journal: Cancer Research (2011)

Abstract OPCML, a GPI anchored tumor suppressor gene is inactivated by somatic methylation in multiple cancers. We previously identified this gene by LOH mapping and demonstrated that it was inactivated by somatic methylation in 80% of ovarian cancers. Restoring OPCML expression by stable transfection suppressed in-vitro growth and in-vivo tumorigenicity. We hypothesized that OPCML might abrogate growth signaling pathways. In SKOV-3 and PEO1, ovarian cancer cell lines with no expression of OPCML, we demonstrated that OPCML negatively regulates a specific repertoire of receptor tyrosine kinases (RTKs) EPHA2, FGFR1, FGFR3, HER2 and HER4, and reciprocally, OPCML siRNA knockdown in normal ovarian surface epithelial cells up-regulates these same RTKs, with no effect on RTKs EPHA10, FGFR2, FGFR4, EGFR, HER3, VEGFR1 and VEGFR3. Example immunoprecipitation experiments revealed that OPCML binds to EphA2, FGFR1 and HER2 extracellular domains with no such interaction to EGFR, thus OPCML binds directly to RTKS that it negatively regulates. We demonstrate that OPCML is located exclusively in the raft membrane fraction and sequesters RTKs that it binds to the raft fraction, leading to polyubiquitination and proteosomal degradation via a cav-1 endosomal mechanism resulting in systems depletion of this specific RTK repertoire, that does not occur with RTKs that OPCML does not bind. We demonstrate that OPCML abrogates EGF mediated phosphorylation of FGFR1, HER2 and EGFR and the downstream phosphosignaling of pErk and pAKT. A recombinant modified OPCML-like protein without a GPI anchor, signal peptide or glycosylation was constructed and expressed in E.Coli. This rOPCML tumor suppressor protein therapeutic caused growth inhibition by apoptosis in 6/7 ovarian cancer cell lines tested with no effect on OPCML expressing normal ovarian surface epithelium by an identical mechanism to the transfected normal protein. rOPCML was then injected intraperitoneally twice weekly in two murine intraperitoneal models of ovarian cancer (nude mouse A2780 and SKOV3) and demonstrated profound inhibition of tumour weight, ascites volume and peritoneal dissemination compared with BSA control. In Summary, the OPCML tumour suppressor mediates its suppressor function by systems level negative regulation of at least 5 RTKs and a recombinant modified derivative is a potent tumor suppressor protein therapeutic in-vitro and in-vivo. 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 1616. doi:10.1158/1538-7445.AM2011-1616
Abstract 3574: Detection of serum CYFRA 21-1 as a biomarker for stratification of ovarian cancer risk in women with a pelvic mass
Authors: Zhong-Qian Li, Robert J. Smalley, Curtis L. Glover, Rachel R. Radwan, Savitha Raju, Katherine L. Falcone, Maryellen Fegely, Kuanglin He, Timothy R. Kettlety
Journal: Cancer Research (2012)

Abstract CYFRA 21-1 is a known lung cancer biomarker. In subjects with ovarian cancer (N = 159) and those with benign gynecological diseases (N = 53), serum CYFRA 21-1 reported a sensitivity (SN) of 44% and a specificity (SP) of 95% for ovarian cancer detection at a cut-off value of 2.4 ng/mL using an ELISA assay (Hasholzner U, et al, 1994). Another report showed a SN of 41% and a SP of 95% for ovarian cancer (N = 37) versus benign ovarian cysts, endometriosis, pelvic inflammatory disease, bowel disease and liver cirrhosis (N = 168) using an ELISA assay (Tempfer C, et al, 1998). We carried out a pilot study to evaluate the serum CYFRA 21-1 as a biomarker for stratification of ovarian cancer risk in women with a pelvic mass. Methods: ARCHITECT CYFRA 21-1 was used to measure the levels of serum CYFRA 21-1. Single point frozen serum samples from 171 female subjects with a pelvic mass were randomly selected from the archive clinical trial described by Moore R et al (2009). Of the 171 subjects, 42 had epithelial ovarian cancer (EOC), 5 with low malignant potential tumor (LMP) and 124 with benign pelvic masses. Results: To stratify EOC from benign pelvic masses and LMP, the following performance was obtained for serum CYFRA 21-1: Notes: The cutpoints were set at 1.2 and 1.8 ng/mL to reach a 75% and 95% SP, respectively. Conclusion: Serum CYFRA 21-1 appears to be a useful biomarker for stratification of EOC from benign pelvic mass and LMP. 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 3574. doi:1538-7445.AM2012-3574
S22 Improved symptoms and quality of life after pulmonary endarterectomy (PEA) in patients with chronic thromboembolic disease (CTED) and borderline pulmonary hypertension (PH)
Authors: D. Taboada, C. Treacey, D. Jenkins, J. P. Zaba, K. Sheares
Journal: Thorax (2011)

<h3>Background</h3> Chronic thromboembolic pulmonary hypertension (CTEPH) is defined by a mean pulmonary artery pressure (mPAP) =25 mm Hg at right heart catheterisation in patients with multiple chronic/organised occlusive thrombi in the pulmonary arteries. PEA is potentially curable and is the treatment of choice for patients with CTEPH. There is a small group of patients with CTED and exertional dyspnoea but with a resting mPAP that does not fulfil criteria for PH in whom PEA may be considered. The outcome of PEA in these patients has not been previously assessed. <h3>Objective</h3> To assess the post PEA functional and haemodynamic outcomes in patients with symptomatic CTED and borderline PH. <h3>Methods</h3> Retrospective data were collected on patients with baseline mPAP of =25 mm Hg who underwent PEA at the UK and Ireland national referral centre between 2002 and 2010. Patients were reassessed 3 and 12 months after surgery. Right heart catheterisation was performed at baseline and 3 months post PEA. <h3>Results</h3> 558 patients underwent PEA at Papworth Hospital between 2002 and 2010. From those, 16 had symptomatic operable CTED and mPAP of =25 mm Hg. Mean age was 45±17 and 69% were female. All survived surgery and are currently alive at follow-up. The median length of stay was 13 days (IQR 6). Results are displayed in the Abstract S22 table 1 as mean ± SD. WHO class data are expressed as percentages. CAMPHOR (Cambridge Pulmonary Hypertension Outcome Review) is a disease specific quality of life questionnaire and scores are expressed as median. <h3>Conclusion</h3> In this small series of patients with CTED and borderline PH, there was a significant symptomatic, haemodynamic and functional benefit from PEA at 1-year. Further research is required to assess the prognostic benefit in this population. We would like to acknowledge the national pulmonary hypertension centres in the UK and Ireland, and support by the Cambridge NIHR Comprehensive Biomedical Research Centre.
Abstract 5732: Mercapturic acid excretion and N7-GA-Gua DNA adduct formation after low dose oral application of acrylamide to rats
Authors: Nico Watzek, Nadine Böhm, Julia Feld, Denise Scherbl, Franz Berger, Karl-Heinz Merz, Alfonso Lampen, Thorsten Reemtsma, Steven R. Tannenbaum, Paul L. Skipper, Matthias Baum, Elke Richling, Gerhard Eisenbrand
Journal: Cancer Research (2012)

Abstract Acrylamide (AA), a genotoxic carcinogen (IARC class 2A), is a food contaminant formed by thermal treatment of food. The margin of exposure (MOE) of AA, representing the distance between the bench mark dose associated with 10% tumor incidence in rats and the estimated average human exposure, is considered to be low and of human health concern. After uptake, AA is partly converted by CYP450 2E1 into the genotoxic epoxide glycidamide (GA). GA forms DNA adducts, primarily at N7 of guanine (N7-GA-Gua). AA and its genotoxic metabolite GA are conjugated to glutathione and excreted via urine as mercapturic acids (MA), namely N-acetyl-S-(2-carbamoylethyl)-cysteine (AAMA), and N-acetyl-S-(2-hydroxy-2-carbamoylethyl)-cysteine (GAMA) which are used as biomarkers for exposure. Female Sprague Dawley (SD) rats were kept on an AA free diet. AA was given by gavage in a broad dosage range, covering single doses of 0.1-10,000 µg/kg bw. Formation of urinary MAs and of N7-GA-Gua DNA adducts in liver, kidney and lung was measured 16 h after application. The lowest dosage of 0.1 µg AA/kg bw did not result in significantly enhanced MA excretion, as compared to untreated controls, found to excrete about 0.8 nmol MA. Since the animals may have ingested at best 0.4 nmol AA/d with the diet, this findings suggests a background level of endogenously formed AA. At the lowest dosage (0.1 µg AA/kg bw), N7-GA-Gua adducts above the limit of detection (LOD, 0.2 adducts/10exp8 nucleotides) were not detected in any organ tested. At 1 µg/kg bw, enhanced adduct levels were found in kidney (around 1 adduct/10exp8 nucleotides) and lung (&amp;lt; 1 adduct/10exp8 nucleotides), but not in liver. At 10 and 100 µg/kg bw, adducts were found in all three organs, at levels not significantly different to those found at 1 µg AA/kg bw (about 1-2 adducts/10exp8 nucleotides). Taken together, the results of this in vivo study allow to conclude that exposure to single doses of AA in the range of human dietary exposure leads to N7-GA-Gua adduct levels in tissues of SD rats at the low end of steady state background DNA lesions of various origin in human and rat tissues. This study was supported by ISIC, the Institute for Scientific Information on Coffee. 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 5732. doi:1538-7445.AM2012-5732
Treatment of Hair Loss
Authors: Vera H. Price
Journal: New England Journal of Medicine (1999)

Hair loss is a common and distressing symptom. With the approval of two drugs that promote hair growth — finasteride and minoxidil — we can now treat patients with some types of hair loss. Both drugs influence the hair-growth cycle and increase the length and diameter of existing hair, although their mechanisms of action differ. In this article, I will focus on the treatment of two common problems, androgenetic alopecia and alopecia areata, both of which involve a reversible alteration of the hair-growth cycle.The Hair-Growth CycleHair growth is cyclic, with phases of growth (anagen), involution (catagen), and rest . . .
309 TEMPORAL REGULATION OF Notch AND Wnt SIGNALLING IN HEPATIC PROGENITOR CELL-MEDIATED HEPATOCELLULAR REGENERATION
Authors: S.E. Minnis-Lyons, L. Boulter, M.J. Williams, R.V. Guest, W.-Y. Lu, O. Sansom, S.J. Forbes
Journal: Journal of Hepatology (2013)
THU0161 Near Misses of ACR/EULAR Criteria Reflects Patient’s Disease Activity Level in Proportion to Patient Global Assessment Level
Authors: I. Yoshii, T. Chijiwa
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> The American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) remission criteria (Boolean criteria) for rheumatoid arthritis (RA) is one of popular index for remission. This index is well known, but not being used even for rheumatologist, because of lack of regularity in patient's global assessment (PGA), which is a part of the core set in Boolean criteria(1). <h3>Objectives</h3> To evaluate near miss of Boolean criteria what means fulfilling three of the four Boolean criteria parameters in clinical practice. <h3>Methods</h3> Since August 2010, we have been treated RA with identical protocol according to T2T recommendations. Five thousand times from 384 RA patients have had chance to measure RA disease activity index such as clinical disease activity index (CDAI), simplified disease activity index (SDAI), Boolean criteria, pain score (PS), and health assessment questionnaire (HAQ-DI). From these indices, Boolean criteria, SDAI, PS, and HAQ-DI were used in this study. Three parameters without PGA fulfilled in Boolean criteria and remission were picked up. These evaluations were qualified as SDAI criteria at each measured time. Distribution of SDAI evaluation criteria was calculated. Measured evaluation was classified into groups according to PGA increment with 1.0 on scale. SDAI remission probability, sensitivity and specificity for SDAI remission were calculated for each division. Average SDAI, average PS, and average HAQ-DI were also calculated for each division, and evaluated with linear regression analysis. <h3>Results</h3> SDAI remission probability for each PGA division was 1.0, 0.97, 0.88, 0.55, 0.67, 0.51, and 0.49, while sensitivity for SDAI remission was 1.0, 0.9981, 0.9842, 0.9671, 0.9437, 0.9353, 0.9194, and specificity was 0.5051, 0.5556, 0.6907, 0.7214, 0.8659, 0.9048, 1.0 for 0, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0 in PGA scale division, respectively. PGA was closely correlated with all of SDAI, PS and HAQ-DI significantly, while regression formula was y=0.5765x + 0.155 (R=0.99283), y=4.522x - 2.3955 (R=0.98530), and y=0.6611x – 0.0463 (R=0.84253), respectively. <h3>Conclusions</h3> These results suggested that PGA in near misses of Boolean criteria reflects disease activity level very strongly. If PGA is within 2.5, both of sensitivity and specificity for SDAI remission demonstrated more than 90%. PGA is also closely related with pain and ADL. We should make consideration to use Boolean criteria with alternative utility. <h3>References</h3> Studenic P., et al., Ann Rheum Dis 2012;69:1702-1705 <h3>Disclosure of Interest</h3> None Declared
Thymic Small Cell Neuroendocrine Carcinoma Displayed on 18F-FDG PET/CT Imaging
Authors: Lei Jiang, Yanli Li, Lijuan Luan, Yongxing Zhang, Hongcheng Shi
Journal: Clinical Nuclear Medicine (2015)

A 52-year-old man presented with chest distress and low back pain for 1 month. CT examination displayed a thymic tumor with the metastases to bilateral lungs as well as mediastinal and bilateral hilar lymph nodes. To evaluate the involved extent of the disease, 18F-FDG PET/CT scan was carried out, which showed that in addition to the thymic mass, multiple foci of abnormally increased FDG activity in the bilateral lungs, neck and chest lymph nodes, and bones were observed. Finally, the biopsy of the mass confirmed the diagnosis of thymic small cell neuroendocrine carcinoma.
A Chilly Fever
Authors: Amanda J. Redig, Anand Vaidya, Christin Price, Joel T. Katz, James H. Maguire
Journal: New England Journal of Medicine (2014)

A 30-year-old man living in Boston presented to the emergency department in late March with fevers and shaking chills. He had been feeling well and in his usual state of health, which included participation in regular outdoor exercise, until approximately 1 week before presentation, when he began to have daily fevers, with temperatures as high as 39.4°C. The fevers were associated with . . .
OC-014 Patients With Intramucosal Carcinoma Arising In Barrett’s Eosophagus Have Similar Outcomes To Those With High Grade Dysplasia: Data From The United Kingdom Registry
Authors: RJ Haidry, M Banks, A Gupta, M Butt, G Fullarton, H Smart, J Morris, R Willert, R Narayanasamy, M Rodriguez-Justo, M Novelli, L Lovat
Journal: Gut (2014)

<h3>Introduction</h3> Mucosal neoplasia arising in Barrett’s oesophagus (BE) can be treated with combined radiofrequency ablation (RFA) and endoscopic mucosal resection (EMR). Once there is submucosal invasion the risk of lymph node metastases increases and surgery is favoured. High grade dysplasia (HGD) and intramucosal carcinoma (IMC) arising from the mucosal layer in BE are defined as separate entities in the revised Vienna classification (category 4.1 and 4.4 respectively). <h3>Methods</h3> We examine prospective data from United Kingdom (UK) registry of patients undergoing RFA/EMR for BE neoplasia over past 5 years to compare outcomes between HGD and IMC patient cohorts. Histological confirmation of HGD or IMC was required on two separate occasions by specialist histopathologists prior to treatment. Before RFA, visible lesions were removed by EMR. Thereafter patients underwent RFA 3 monthly following which biopsies were taken at 12 months for clearance of dysplasia (CR-D) and BE (CR-IM). Twelve month outcomes, frequency of EMR, cancer progression and long term durability in both groups were examined. <h3>Results</h3> To date 367 patients with HGD and 125 with IMC have been treated. There is no difference in age, sex, baseline BE length between the 2 groups. EMR prior to RFA is far more prevalent in IMC cohort than HGD patients (78 vs. 45%, P &lt; 0.0001). Patients had an average of 2–3 RFA treatments over 12 months (range 1–6) in both cohorts. Rescue EMR after starting RFA for new lesions was similar in both groups (HGD 7%, IMC 6.5%). CR-D and CR-IM in the HGD cohort was 85 and 69% respectively at 12 months. This was not significantly different in the IMC cohort (86 and 71%, p = 0.7). Overall progression to invasive cancer was not significantly different in either cohort (HGD 4.1%, IMC 7.2%). Kaplan Meir survival statistics did not show any difference in long term durability of successful neoplasia treatment in both groups (p = 0.9, log rank test), median follow up 20 months. <h3>Conclusion</h3> We report one of the largest series of patients undergoing endoscopic therapy for IMC arising in BE. Patients with IMC are more likely to have visible lesions that require EMR prior to RFA than those with HGD. However, once all visible lesions are removed, there is no statistical difference in clinical outcomes between the cohorts. Minimally invasive endoscopic therapy with RFA/EMR is a safe and effective treatment in patients with IMC.<i> All collaborators of the UK RFA registry are acknowledged for their contributions to this work</i> <h3>Disclosure of Interest</h3> None Declared.
THU0200 Comparison of Quantiferon-TB Test and TST in Routine Practice During Anti-TNF Treatment
Authors: U. Kalyoncu, L. Kilic, O. Karadag, S. A. Bilgen, S. Kiraz, A. Akdogan, I. Ertenli
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Tuberculosis is a major infectious problem during anti-TNF treatments in tuberculosis prevalent countries. BCG vaccine may influence tuberculosis skin test (TST) results in these countries. Quantiferon-TB test may replace TST test for screening of tuberculosis. <h3>Objectives</h3> To assess quantiferon-TB and TST tests positivity for assessment of prophylactic anti-tuberculosis treatment. <h3>Methods</h3> Hacettepe University Biological Database (HUBİD) include approximately 1800 patients since 2005. TST test was used between 2005 to 2011 for the assessment of latent tuberculosis. After 2011 in HUBİD, quatiferon-TB test was used for this purpose in routine clinical practice. We searched database for TST (positive (&gt;5mm) and negative), quantiferon-TB (positive and negative), and starting anti-tuberculosis prophylaxis. <h3>Results</h3> TST results were known in 846 patients. Seven hundred six (83.4%) of patients had positive TST results, and anti-tuberculosis prophylaxis were started in those patients. Quantiferon-TB results were known in 387 patients, since 2011. Eighty five of 387 (21.9%) patients had positive quantiferon-TB test. Forty six patients had both TST and quatiferon-TB test results. Ten of 46 patients (21.7%) had positive TST and positive quantiferon-TB test. Those patients were taken anti-tuberculosis prophylaxis. Twenty five of 46 (54.3%) patients had positive TST and negative quatiferon-TB test. Nine of 46 (19.6%) patients had both negative TST and quatiferon-TB. <h3>Conclusions</h3> Isoniazid prophylaxis has important advers effect such as liver dysfunction and neuropathy. Almost 80% of patients were received INAH prophylaxis when TST test used for screening. However, only almost 20 % of patients were received INAH prophylaxis when quantiferon-TB test were used. Concordance of both test is very low particularly countries under routine BCG vaccine. Closer follow-up of patients who were not put on isoniazid prophylaxis according to quantiferon-TB results are mandatory and the results of this follw-up may change approach to tuberculosis prophylaxis. <h3>Disclosure of Interest</h3> None Declared