tbuckley/cabot-search huggingface dataset:
FRI0182 Pharmacokinetics and immunogenicity of mavrilimumab administered subcutaneously in subjects with rheumatoid arthritis
Authors: C.-Y. Wu, X. Chen, H. Lu, E. Esfandiari, F. Magrini, A. Godwood, P. Ryan, C. Kane, L. Roskos, B. Wang
Journal: Annals of the Rheumatic Diseases (2013)

Background Mavrilimumab is a high-affinity, fully human immunoglobulin G (IgG) monoclonal antibody that selectively binds to the α subunit of GM-CSF receptor (GM-CSFRα). A Phase 2a randomized, double-blind, placebo-controlled, multiple ascending dose study was conducted to evaluate the efficacy, safety, pharmacokinetics (PK) and immunogenicity of mavrilimumab in subjects with at least moderately active rheumatoid arthritis (RA). Objectives To characterize the PK and immunogenicity of mavrilimumab after multiple subcutaneous administrations to RA patients (10-100 mg Q2W x7). Methods Serum samples for mavrilimumab concentration determination and the detection of the presence of anti-drug antibodies (ADA) were collected from all RA subjects at pre-designated timepoints, and analyzed using validated electrochemiluminescence assay (PK) or enzyme-linked immunosorbent assay (ADA). Noncompartmental PK data analysis was performed using WinNonlin (Pharsight Corp, St Louis, MO). Exposure-response relationship was assessed using a population modeling approach. Results Maximum serum mavrilimumab concentrations (Cmax) were observed approximately 3 days following SC administrations. The PK exposure (Cmax and AUC) of mavrilimumab increased more than dose-proportionally across the investigated dose range (10-100 mg). Mavrilimumab was cleared more rapidly at lower dose levels due to the GM-CSF receptor-mediated clearance. The average PK half-life was approximately 13 days at 100 mg dose level when GM-CSFRα was fully occupied by mavrilimumab. Three (3.8%) placebo subjects and 20 (13%) mavrilimumab-treated subjects had positive ADA during the study period. The relationship between PK and RA disease activity was adequately described by a direct Emax model. Conclusions The observed mavrilimumab PK profiles in this Phase 2a study were consistent with prior projections from a mechanistic population model1. The PK parameters of mavrilimumab following SC dosing are typical of a monoclonal antibody with target-mediated disposition. The PK and immunogenicity properties of mavrilimumab, and the direct exposure-response relationship support further clinical development of mavrilimumab for the treatment of RA. 1. Wang, B. et. al., Mechanistic Modeling of Antigen Sink Effect for Mavrilimumab Following Intravenous Administration in Patients With Rheumatoid Arthritis. Journal of Clinical Pharmacology (in press), 2012 Disclosure of Interest C.-Y. Wu Employee of: Medimmune, X. Chen Employee of: Medimmune, H. Lu Employee of: Medimmune, E. Esfandiari Employee of: Medimmune, F. Magrini Employee of: Medimmune, A. Godwood Employee of: Medimmune, P. Ryan Employee of: Medimmune, C. Kane Employee of: Medimmune, L. Roskos Employee of: Medimmune, B. Wang Employee of: Medimmune
SP0203 How Patients Can Contribute to and Benefit From HTA Research to Improve Equity in Europe
Authors: M. De Wit
Journal: Annals of the Rheumatic Diseases (2013)

<h3></h3> HTA research (Health Technology Assessment) has many benefits for people with rheumatic diseases. It is important to guarantee the effectiveness, safety and affordability of new medications, devices and recommendations that enter the market. Although the potential benefits of HTA research for patients are obvious, they are not always accomplished. Especially in times of economic crisis and radical health policy reforms, patients are confronted with serious consequences related to the accessibility and affordability of effective treatments. The lack of active involvement of patients and patient organisations in the different phases of HTA research is an important barrier for optimizing the HTA process. Patient organisations can play an important role in the prioritization, initiation and conduct of HTA research as well as in shaping health policies that take the needs and preferences of patients into account. In this presentation the success factors of existing international examples of effective involvement of patient organisation in HTA research will be explored and assessed for their transferability to the area of rheumatology. <h3>Disclosure of Interest</h3> None Declared
Invasive Infections Due to a Fish Pathogen,<i>Streptococcus iniae</i>
Authors: Mitchell R. Weinstein, Margaret Litt, Daniel A. Kertesz, Phyllis Wyper, David Rose, Mark Coulter, Allison McGeer, Richard Facklam, Carola Ostach, Barbara M. Willey, Al Borczyk, Donald E. Low
Journal: New England Journal of Medicine (1997)

Streptococcus iniae is a pathogen in fish, capable of causing invasive disease and outbreaks in aquaculture farms. During the winter of 1995–1996 in the greater Toronto area there was a cluster of four cases of invasive S. iniae infection in people who had recently handled fresh, whole fish from such farms.
SAT0419 Comparison of 18FDG-PET and MRI of the shoulder in patients with rheumatoid arthritis
Authors: Y. Yonemoto, K. Okamura, T. Kaneko, T. Kobayashi, K. Takeuchi, K. Takagishi
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Rheumatic diseases including rheumatoid arthritis (RA) have been investigated using <sup>18</sup>FDG-PET (PET). A relationship has been identified among the disease activity, the progress of the joint destruction and the PET findings. In addition, there have so far been few reports about the relationship between PET and synovitis in magnetic resonance imaging (MRI) of the wrist and knee. However, the relationship between synovitis in MRI and the uptake in PET of the shoulder joints is unclear, as is the cut-off line of the standardized uptake value (SUV). <h3>Objectives</h3> The aim of this study is to assess the PET findings and synovitis of the shoulder joints in the MRI findings in RA patients. <h3>Methods</h3> Forty-three shoulders in 42 patients with RA were assessed with PET and MRI. The mean age (range) was 54 years (36–75) and the mean disease duration was 9 years (1–40). <sup>18</sup>F-FDG uptake was quantified using the maximum pixel value of the SUV. Synovitis in shoulder MRIs was examined in the axillary pouch (AP), subacromial bursa (SAB), subdeltoid bursa (SDB), rotator interval (RI) and acromioclavicular joint (ACJ). The relationships between synovitis and SUV were examined. <h3>Results</h3> The mean PET SUVmax (range) was 1.99 (0.87-6.17). MRI showed that 8 of 43 shoulders had synovitis in the AP, 17 in the SAB, 12 in the SDB, 16 in the RI and 5 in the ACJ. The total number of synovitis sites was significantly correlated with the SUV (R=0.72, P&lt;0.01). The area under an ROC curve was 0.88. The sensitivity was 0.833 and specificity was 0.842 with a SUV cut-off line of 1.50. <h3>Conclusions</h3> The SUV of the PET reflected synovitis of the shoulder MRI in patients with RA. The cut-off level of the SUV was 1.50 in an RA shoulder joint. <h3>References</h3> Polisson RP, Schoenberg OI, Fischman A, Rubin R, Simon LS, Rosenthal D, Palmer WE. Use of magnetic resonance imaging and positron emission tomography in the assessment of synovial volume and glucose metabolism in patients with rheumatoid arthritis. Arthritis Rheum 1995; 38(6): 819-825 Palmer WE, Rosenthal DI, Schoenberg OI, et al. Quantification of inflammation in the Wrist with Gadolium-enhansed MR Imaging and PET with 2-IF-181-Fluoro2-deoxy-D-glucose. Radiology 1995; 196: 647. Beckers C, Jeukens X, Ribbens C, André B, Marcelis S, Leclercq P, Kaiser MJ,Foidart J, Hustinx R, Malaise MG. (18)F-FDG PET imaging of rheumatoid knee synovitis correlates with dynamic magnetic resonance and sonographic assessments as well as with the serum level of metalloproteinase-3. Eur J Nucl Med Mol Imaging 2006; 33(3):275-280 <h3>Disclosure of Interest</h3> None Declared
AB0704 Evaluation of nailfoldvideocapillaroscopy in familial mediterranean fever patients
Authors: A. Balkarli, Ü. Ozkan, N. Özhan, S. Temel, V. Cobankara
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Familial Mediterranean Fever (FMF) is an inflammatory disease characterized by synovitis and pleurotic attacks. It is an autosomal recessive disorder, and the exact etiology is unknown. 7% of patients can have Henoch-Schönleinpurpura and polyarthritis nodosa. <h3>Objectives</h3> We aimed to determine microvascular abnormalities in FMF patients with nailfoldvideocapillaroscopy. <h3>Methods</h3> We included non-smoker 29 FMF patients and 30 healthy individuals. Patients were reviewed about smoking, Raynaud's phenomena and ischemic ulcers. Patients who had comorbidities including hypertension, smoking and Raynaud's phenomena were not included in this study. A computerized form including demographic, clinical and para-clinical features was used to collect data. We used videocapillaroscope (x200) for capillaroscopic evaluation. Patients were put to hand rest (protection from trauma) 2 weeks before the capillaroscopic procedure and hands were held in room temperature at least 20 minutes on the day of the procedure.8 fingers excluding thumbs (total of 32 fields of one millimeter right and left from each finger median line) were evaluated independently by 2 doctors, and signs were recorded to patient follow-up form. We evaluated capillary quantity, microhemorrhage, ectasied capillaries (neat-not neat), megacapillaries, avascular space, bushy capillaries, meandering capillaries, neovascularization and bizarre capillaries with nailfoldvideocapillaroscopy. Ectasied capillaries were defined as capillary diameter &gt;0.02 nm, megacapillaries as &gt;0.05 nm, and microhemorrhage was defined as hemorrhage determined in at least two fingers without trauma. <h3>Results</h3> Mean age of patients was 29.5±12 (16-60), disease starting age was 20.9±9.66 (7-49), and disease duration was 8.69±8 (1-33) years. We observed megacapillary and microhemorrage in one patient (3.44%), tortuosity in 11 patients (37.93%), and bizarre capillary in 7 patients (24.13%). No association was found between capillaryscopic pathologies and age, disease starting age, disease duration and clinical signs. <h3>Conclusions</h3> Except one patient with microhemorrage and megacapillary, all signs we observed in this study were nonspecific capillaroscopic findings and did not explain the importance of these in FMF patients. Further studies can be made to understand videocapillaroscopic signs with larger study group. <h3>Disclosure of Interest</h3> None Declared
Abstract P5-03-06: Progesterone Activates MAPK Pathway in Estrogen Induced Mammary Carcinogenesis
Authors: T Boopalan, A Arumugam, A Delgado, J Parada, P Agullo, R. Lakshmanaswamy
Journal: Cancer Research (2010)

Abstract In women, breast cancer is the most prevailing endocrine-related malignancy. Epidemiological and experimental studies argue that estrogens are central to its etiology. Estrogen-induced carcinogenesis in ACI rats is highly relevant as a model for human breast cancer. These estrogen-induced cancers exhibit aneuploidy, as do invasive ductal mammary carcinomas in women. It has been demonstrated that ovary intact ACI rats given estrogen induced high incidence of mammary cancers while ovariectomized rats given the same dose of estrogen for the same length of time did not induce mammary cancers. Recently, we demonstrated that ovariectomized ACI rats given estrogen plus progesterone had a high incidence of mammary cancer. In this context, it is essential to understand the possible role of progesterone, if any, as the other main ovarian hormone in mammary carcinogenesis. Our goal was to determine the role of progesterone in mammary cancer development by using carcinogenesis induced solely by hormones in ACI rats. To achieve our goal, we designed the following experiment. Ovary intact and ovariectomized rats were used in this study. The groups (n=30) tested were as follows: 1) ovary intact control (no hormone treatment); 2) ovary intact rats given 30 mg estradiol; 3) ovary intact rats given 30 mg estradiol plus 30 mg mifepristone; 4) ovary intact rats given 30 mg progesterone; 5) ovariectomized control (no hormone treatment); 6) ovariectomized rats given 30 mg estrogen; and 7) ovariectomized rats given 30 mg estradiol plus 30 mg progesterone. Mammary glands were surgically excised and snap frozen in liquid nitrogen and stored at -80°C from a subset (n=4) of intact animals after four weeks of treatment and ovariectomized rats after twelve weeks of treatment. In rest of the animals mammary carcinogenesis was followed for nine months. As expected, estradiol induced mammary cancers in ovary intact rats and not in ovariectomized rats. Addition of progesterone to ovariectomized rats treated with estradiol induced high incidence of mammary cancer. Mifepristone treatment inhibited mammary carcinogenesis in ovary intact rats receiving estradiol. Pathway focused microarray analysis of mammary glands from the rats of different groups and treatment indicated alterations in apoptosis, MAPK and PI3K pathways. Estrogen plus progesterone treatment down regulated apoptotic genes such as Apaf1, Bad, Bax, Bid, Casp9 and up regulated Mapk3, Grb10, Itgb1, PrKca, Prkcz and Map4k1, Map2k1ip1, Mapk8ip2, Mapkapk5 in PI3K and MAPK pathways respectively when compared with estrogen alone treatment. We have observed differences both at transcriptional and translational levels. Our results clearly demonstrate the significance of progesterone in mammary carcinogenesis. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-03-06.
AB0955 Determining Optimal Hand Position for Reliable Metacarpophalangeal Joint Width Measurements Using Volumetric Methodology by Hr-Pqct: Table 1
Authors: C. Barnabe, O. Montpellier, S.L. Manske, S.K. Boyd
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Joint space narrowing is an important outcome measure in rheumatoid arthritis, linked tightly to function and disability. High-resolution peripheral quantitative computed tomography (HR-pQCT) allows detection of bone margins with high precision. Based on this capability, we have devised a software script to quantify volumetric joint space width based on the method of "fitting maximal spheres"<sup>1</sup>. The position-dependence of this method needs to be determined to be reliably applied to longitudinal studies. <h3>Objectives</h3> To assess the reliability of 3D volumetric joint space measurements with 5 degree variations in hand position, between 0 and 30 degrees of flexion, at the metacarpophalangeal (MCP) joints. <h3>Methods</h3> Six cadaver hands were imaged with HR-pQCT, with image acquisition of the 2nd and 3rd MCP joints (n=12 joints) using a SPECTRA-endorsed imaging protocol<sup>2</sup>. Using a positioning device, the MCPs were placed at 7 different angles of flexion (0, 5, 10, 15, 20, 25 and 30 degrees), and actual angles were verified from the acquired images in the y-z plane post-hoc. Descriptive statistics were used to calculate the mean, median, minimum, and maximum joint space widths and total volume measurements, by degree of angulation. The root-mean-square coefficient of variance (RMSCV) was calculated for individual joints to determine the variability caused by angulation. <h3>Results</h3> The differences in positioned vs measured angle were small for 0, 5, and 10 degrees, but significant for &gt;15 degrees of flexion, with the actual measurement ranging from 20.8 to 32.5 at 30 degrees. Despite this, the volumetric joint space width measurement gave robust results in line with accepted metrics for HR-pQCT, with a RMSCV for mean joint space width of 6.2% (SD 2.8), median joint space width of 6.5% (SD 2.4), maximum joint space width of 5.3% (SD 2.9), and 5.8% (SD 3.6) for total volume. <h3>Conclusions</h3> Our 3D volumetric measurement method of joint space width for images acquired with HR-pQCT technology is reliable for MCP flexion angles of 0 to 30 degrees. Performance is optimized between 0 and 10 degrees of flexion, and care should be given to remaining in this parameter for longitudinal or repeated measures studies. <h3>References</h3> Barnabe C, Buie H, Kan M et al. Med Eng Physics 2013;35:1540-1544. Barnabe C, Feehan L. J Rheumatol 2012;39:1494-5. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.3336
Abstract 4298: Identification of subpopulation with more defined characteristics of cancer stem cells in endometrial cancer
Authors: Mitsuhiro Nakamura, Satoru Kyo, Xiuzhi Zhang, Masahiro Takakura, Manabu Hashimoto, Yasunari Mizumoto, Noriko Mori, Toshiyuki Sasagawa, Masaki Inoue
Journal: Cancer Research (2010)

Abstract [Background] Cancer stem cells (CSCs) have been known to be the major source of tumor propagation and might be an attractive therapeutic target. Our previous study showed that CD133+ Ishikawa and MFE 280 endometrial cancer cells have the ability of tumorigenicity, self-renewal and differentiation capacity in vitro and in vivo, while CD133- cells did not. Furthermore, CD133+ cells showed more resistance to cisplatin- or paclitaxel-induced cytotoxicity than CD133- cells. These results indicate that CD133 is the CSC maker in endometrial cancer cells. In the present study, we sought to identify the subpopulation with more defined CSC characteristics in endometrial cancer. [Methods] We examined the expression of CD133, CD44 and Hoechst 33342 side population (SP) marker by flow cytometry (FACS) in endometrial canecr cells. MIcroarray analysis was performed to investigate the molecules essential for the CSCs characteristics by 3D-Gene chip (TORAY). [Results] FACS analysis demonstrated that in the CD133+ Ishikawa and MFE280 cells, about 50% cells showed CD44 expression, whereas about 20% cells expressed it in CD133- cells. Isolated CD44+/CD133+ cells showed more extensive proliferation and tumorigenicity, compared with CD44+/CD133-, CD44-/CD133+ and CD44-/CD133- cells, indicating that the CD44+/CD133+ endometrial cancer cells have the potential of more defined CSCs. On the other hand, the ratio of SP fraction was similar in CD133+ and CD133- cells. Microarray analysis showed elevated expression of MT1-MMP and VEGF in CSCs, compared to non-CSCs. Invasion assay revealed that CSCs have more invasive property than non-CSCs. The inhibition of MT1-MMP gene by siRNA significantly reduced the invasive ability of CSCs. These results suggest that MT1-MMP is one of the critical molecules that generate biological features of CSC and may be a potential therapeutic target in endometrial cancer. [Conclusions] We demonstrated that CD44+/CD133+ cells might be more defined CSCs in endometrial cancer and identified important molecules essential for characterizing endometrial CSCs that might be a therapeutic target of this tumor type. 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 4298.
What we (don't) know about what we know
Authors: Shlomi Sher, Piotr Winkielman
Journal: Behavioral and Brain Sciences (2014)

Abstract The hypothesis of unconscious influences on complex behavior is observationally equivalent to the dissociability of cognition and metacognition (reportability). The target article convincingly argues that evidence for unconscious influence is limited by the quality of the metacognitive measure used. However, it understates the empirical evidence for unconscious influences and overlooks considerations of cognitive architecture that make cognitive/metacognitive dissociations likely.
A Prospective, Randomized, Placebo Controlled Study of Simvastatin/Chemotherapy Effectiveness in Metastatic Breast Cancer Patients
Authors: L.A. Youssef, H. Alarfi, M.I. Salamoon, M. Kadri, M. Alammar, M.A. Haykal, A. Alseoudi
Journal: Annals of Oncology (2014)
P240 Smartinhalers - A New Approach To Assessing Adherence In Difficult Asthma
Authors: P. Hall, M. Bracken, D. Winch, P. Nagakumar, A. Bush, S. Saglani, L. Fleming
Journal: Thorax (2014)

<h3>Introduction</h3> Poor adherence is one of the key determinants of sub-optimal asthma control in children. Correctly identifying children with poor adherence can avoid unnecessary escalation of treatment and enable a targeted adherence intervention. <h3>Objective</h3> To use electronic monitoring devices (Smartinhalers) to measure adherence to inhaled corticosteroids (ICS) in children with problematic severe asthma (PSA) and compare the data with prescription uptake and symptoms during the monitoring period. <h3>Methods</h3> Smartinhalers were issued to patients for a 6–8 week study period as part of an established nurse led assessment in a tertiary referral centre. Advice regarding adherence and the purpose of the Smartinhalers was explained to all children and their parents. Lung function, bronchodilator reversibility, exhaled nitric oxide (FENO), mini paediatric asthma quality of life questionnaire (mPAQLQ), and asthma control test (ACT) were recorded at baseline and follow up. Wilcoxon signed ranks was used to compare visit 1 and visit 2 data. GP prescription uptake for ICS and number of salbutamol canisters issued in past year were obtained. <h3>Results</h3> 33 children (21 male), median age 13 (5–17) years) were issued with Smartinhalers. 15 had adherence &gt;80%, 14 between 50–80% and 4 &lt; 50%. ACT and mPAQLQ improved significantly over the monitoring period (Figures 1 and 2). Children with a prescription uptake of &lt;80% had a significant improvement in ACT compared to those with pick up of ≥80% (median change 3.5 (IQR 0.75–7.25) vs 0 (-4–3)) and a non-significant trend towards improvements in FEV1 and BDR. There was no relationship between prescription uptake and Smartinhaler adherence or salbutamol inhalers collected. <h3>Conclusion</h3> Even when children know they are being monitored over half used &lt;80% of the prescribed dose. Improvements in objective markers of asthma control during the monitoring period can help to identify those who were previously poorly adherent. Smartinhalers are useful tools in the assessment of adherence in conjunction with GP prescriptions and clinical observations.
The Effect on Serum Cholesterol Levels of Coffee Brewed by Filtering or Boiling
Authors: Annette A.A. Bak, Diederick E. Grobbee
Journal: New England Journal of Medicine (1989)

Previous reports have indicated that coffee consumption may increase serum cholesterol levels. We studied the effects of coffee prepared by two common brewing methods (filtering and boiling) on serum lipid levels in a 12-week randomized trial involving 107 young adult subjects with normal serum cholesterol levels. After a three-week run-in period during which they all consumed filtered coffee, the participants were randomly assigned to one of three groups receiving four to six cups of boiled coffee a day, four to six cups of filtered coffee a day, or no coffee, for a period of nine weeks. As compared with the change from base line in the filtered-coffee group, the serum total cholesterol level Increased after the consumption of boiled coffee by 0.48 mmol per liter (95 percent confidence limits, 0.13 and 0.83), and the low-density lipoprotein cholesterol level increased by 0.39 mmol per liter (95 percent confidence limits, –0.04 and 0.82). There was no significant difference in the change in serum total or low-density lipoprotein cholesterol levels between the filtered-coffee group and the group that drank no coffee. The levels of high-density lipoprotein cholesterol and apolipoproteins were not affected by boiled or filtered coffee. We conclude that drinking filtered coffee does not affect serum lipld levels. The consumption of boiled coffee, however, has an effect on serum cholesterol levels amounting to a mean net increase of 10 percent of the base-line level after nine weeks. (N Engl J Med 1989; 321:1432–7.)