tbuckley/cabot-search huggingface dataset:
A6.14 Dysregulations in the sphingolipid pathway in sle patients
Authors: A Checa, H Idborg, D Garcia Sar, PJ Jakobsson, CE Wheelock, I Gunnarsson
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background and objectives</h3> Systemic lupus erythematosus (SLE) is an autoimmune disease with a heterogeneous presentation of symptoms from joints, skin, kidneys, central nervous system, lungs, and the cardiovascular system. There is no cure for SLE and development of novel drugs and biomarkers of effective treatment is needed. Sphingolipids are bioactive signalling molecules involved in the regulation of cell growth, differentiation and apoptosis. Dysregulation of single sphingolipids has been described in several diseases with an inflammatory component and sphingosine-1-phosphate (S1P) agonist (Fingolimod) is investigated as treatment in SLE. Therefore, the sphingolipid pathway has arisen as very important compounds to study in respect to SLE pathogenesis. The compounds of the sphingolipid pathway are highly correlated and simultaneous measure of several sphingolipids in an 'omics' like analysis is expected to provide more information than compounds individually determined. Our objective is to screen the sphingolipid pathway in patients with SLE compared to healthy controls. In addition we aim to study if the altered sphingolipids will be normalised after treatment. <h3>Materials and methods</h3> EDTA-plasma from 107 SLE female patients were screened for 34 different sphingolipids by liquid chromatography tandem mass spectrometry (LC-MS/MS) and compared to matched healthy population-based donors (n = 23). In addition, female SLE patients (n = 22) were analysed before and after induction of remission treatment. <h3>Results</h3> SLE patients were found to exhibit an altered sphingolipid profile compared to controls. Significantly (p &lt; 0.01) increased levels of C16:0- and C24:1-ceramides, C16:0, C18:0 and C24:1-hexosylceramides and decreased levels of S1P were found in SLE patients compared to controls. The observed higher levels of ceramide to S1P ratios in SLE patients may reflect the blockage of the pathway that is controlled by ceramidase and can be inhibited by nitric oxide. These alterations were associated with SLAM and SLEDAI clinical scores and were normalised after induction of remission treatment. <h3>Conclusions</h3> This work shows the importance of performing a holistic approach targeting the different molecules of the sphingolipid pathway. Our results show dysregulations in circulating sphingolipids in patients with SLE and normalised after treatment, suggesting that sphingolipids may be useful markers of disease progression and possible drug targets.
Abstract 1880: Incorporating protein levels with genetic variation and gene expression in sensitivity to chemotherapy
Authors: Amy L. Stark, Ronald J. Hause, Lidija K. Gorsic, Nirav N. Antao, Sophie H. Chung, Daniel F. Gill, Kevin P. White, Richard B. Jones, M. Eileen Dolan
Journal: Cancer Research (2012)

Abstract Genome-wide studies of genes important in chemotherapeutic sensitivity or disease susceptibility and progression have primarily relied on mRNA expression levels; however, mRNA expression levels do not always accurately reflect downstream protein abundances. We have applied a novel technology, microwestern arrays, along with reverse phase lysate arrays, to evaluate the role that over 400 transcription factor and signaling proteins play in mediating cellular sensitivity to ten chemotherapeutic agents. Utilizing unrelated International HapMap lymphoblastoid cell lines derived from the Yoruba population, we evaluated the relationship between protein abundances, genetic variation, microRNA and mRNA expression, and chemotherapeutic-induced cytotoxicity and apoptosis. Using ∼12 million single nucleotide polymorphism (SNPs) imputed from the 1000 Genomes Project, we identified SNPs associated with protein abundance (protein quantitative trait loci, pQTLs) and SNPs associated with chemotherapeutic sensitivity (drug quantitative trait loci, dQTLs). Chemotherapeutic agents included platinating agents, antimetabolites and microtubule inhibitors. For cytarabine there was a significant (p&amp;lt;0.0001) enrichment of pQTLs in the SNPs associated with cytotoxicity and apoptosis. We also identified 71 protein levels associated with cytarabine-induced cytotoxicity and apoptosis at p&amp;lt;0.05. One protein, ATF2, was associated (p&amp;lt;0.006) with both high (40 µM) and low (5 µM) dose cytarabine-induced apoptosis and there were six SNPs associated with apoptosis phenotypes (p&amp;lt;0.00007) that also associated with the protein level (p&amp;lt;0.00009). Knockdown of ATF2 protein with siRNA resulted in 40-51% of endogenous levels concomitant with a significant increase in apoptosis induced by cytarabine at both doses (p=0.001). This relationship was not identified in analyses correlating mRNA with phenotypes thus demonstrating the importance of incorporating protein levels into studies that aim to identify potential biomarkers. By incorporating genetic variation, mRNA, protein, and microRNA levels with chemotherapeutic sensitivity, the complex role of the genetic architecture in cellular chemotherapy response through its effects on expression and protein can be better understood. This study has broad potential for application to other chemotherapeutic drugs and complex traits. 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 1880. doi:1538-7445.AM2012-1880
HMGB1 expression in hormonally independent breast carcinoma
Authors: D. R. Budman, M. F. Barginear, A. Goyal, S. Chavan, L. Yang, A. Callabro, T. P. Bradley, K. J. Tracey
Journal: Journal of Clinical Oncology (2008)

14655 Background: Estrogen and estrogen receptors (ER) play key roles in normal breast development and breast cancer progression; this was observed more than 100 years ago. Hormonal receptor expression correlates with cellular turnover rates, nuclear grade, degree of histological differentiation, and disease-free intervals. The function of ER is modulated by binding of ER to estrogen response elements and mediated by additional cellular proteins. High mobility group box protein1( HMGB1) is a nuclear protein that has been implicated in modulating ER gene interactions, particularly DNA bending. Here we explore HMGB1 expression in breast cancer cell lines. Methods: ER- negative breast cancer cell lines MCF7/adr, MDA-MB-231, BT-20, and ER-positive breast cancer cell lines MCF7/cst, MDA-MB-13, and BT-474 were obtained from the American Type Culture Collection (Rockville, USA). HMGB1 levels were evaluated by quantitative immunoblotting technique. The detection limit of HMGB1 was achieved at concentrations above 1 ng/ml. Each experiment was repeated at least five times to ensure reproducibility. Results: ER-negative breast cancer cell lines expressed HMGB1 levels 3–4 times higher than ER-positive breast cancer cell lines, as shown in Table 1. Conclusion: To our knowledge this is the first report to show elevated expression of HMGB1 expression in ER-negative breast carcinoma. These variations may contribute to different the biological characteristics and therapeutic responses among breast tumors. Table 1: HMGB1 expression is elevated in ER-negative breast cancer ER− ER+ 450 100 325 200 430 110 Mean 401.67 136.67 Standard Deviation 54.82 44.97 Standard Error of the Mean 31.65 44.97 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Critical Therapeutics Inc. (CRTX)
Resilient cerebellar theory complies with stiff opposition
Authors: Allan M. Smith
Journal: Behavioral and Brain Sciences (1996)

In response to several requests from commentators, an unambiguous definition of time-varying joint stiffness is provided. However, since a variety of different operations can be used to measure stiffness, a problem for quantification admittedly still exists. Several commentaries pointed out the advantage of controlling joint stiffness in optimizing the speed-accuracy trade-off known as Fittss law. The deficit in rapid reciprocal movements and the impact on joint stiffness inhibition caused by cerebellar lesions is clarified here, as the target article was apparently misinterpreted by some readers. In response to the challenge that there is little consensus among cerebellar physiologists, several areas of tacit agreement with other theories of cerebellar function are enumerated. An alternative interpretation of studies showing a transient activation of the cerebellum in motor learning is suggested. Finally, the relationship between the command signals generated by supraspinal centers such as the cerebellum and spinal interneuron networks controlling muscle synergies is discussed.
Neuropathies Associated with Paraproteinemia
Authors: Allan H. Ropper, Kenneth C. Gorson
Journal: New England Journal of Medicine (1998)

A number of common disorders of the peripheral nervous system, termed paraproteinemic neuropathies, are closely connected with the presence of excessive amounts of an abnormal immunoglobulin in the blood. These immunoglobulins can be detected by immunoelectrophoresis or the more sensitive immunofixation test. An estimated 10 percent of idiopathic polyneuropathies are of this type.13 The anomalous blood proteins are usually monoclonal (termed M protein or M spike) and are the product of a single clone of plasma cells. They are clinically important because some of them have the properties of antibodies directed at components of the myelin or the axolemma. . . .
OP0028 The Disease Modifying Effect of Strontium Ranelate in a Phase III Knee Osteoarthritis Study (SEKOIA) Using Quantitative Magnetic Resonance Imaging: Reduction in Bone Marrow Lesion Size Associated with Cartilage Protective Effect
Authors: J. Martel-Pelletier, C. Roubille, J.-P. Raynauld, F. Abram, M. Dorais, P. Delorme, J.-P. Pelletier
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> To explore using quantitative magnetic resonance imaging (qMRI) the disease modifying effect of strontium ranelate (SrRan) treatment on the cartilage volume loss and bone marrow lesions (BMLs) in a subgroup of patients from a Phase III clinical trial on human knee osteoarthritis (OA) (SEKOIA). <h3>Methods</h3> Patients with primary symptomatic knee OA were randomized to receive either SrRan 1 g or 2 g/day or placebo. MRI was performed at baseline, 12, 24, and 36 months. The changes in knee cartilage volume loss and BMLs were assessed in the global joint and subregions. Missing values were imputed and the analyses were adjusted according to Bonferroni. <h3>Results</h3> In the subgroup of patients with MRI, the distribution of patients (n=330) was 113, 105, and 112 for SrRan 1 g/day, 2 g/day, and placebo, respectively. There were no between-group differences at baseline with regard to demographics, clinical symptoms, or imaging characteristics. Treatment with SrRan at 2 g/day significantly decreased the loss of cartilage volume on the tibial plateau at 12 (p=0.002) and 36 months (M36) (p=0.003). At M36, in patients with BML at baseline, the BML score decreased in the two treatment groups compared to an increase in the placebo group in the medial compartment (p=0.002 and p=0.001 in the SrRan 1 g/day and 2 g/day groups, respectively). In those patients, SrRan 2 g/day significantly (p=0.023) decreased the cartilage loss at M36 in the medial tibial plateau compared to placebo, whereas SrRan 1 g/day did not (p=0.763). <h3>Conclusions</h3> In knee OA patients, treatment with SrRan 2 g/day was found to have a beneficial effect both on cartilage and subchondral bone by significantly reducing the cartilage volume loss in the tibial plateau and the progression of BML in the medial compartment. <h3>Disclosure of Interest</h3> J. Martel-Pelletier Shareholder of: ArthroLab Inc, Grant/research support from: Servier, Consultant for: Servier, ArthroLab Inc, C. Roubille: None Declared, J.-P. Raynauld Consultant for: ArthroLab Inc, F. Abram Employee of: ArthroLab Inc., M. Dorais: None Declared, P. Delorme: None Declared, J.-P. Pelletier Shareholder of: ArthroLab Inc, Grant/research support from: Servier, Consultant for: Servier, ArthroLab Inc
The Immunoglobulin Diagnosis, Evaluation, and Key Learnings (IDEaL) Patient Registry: Analysis of Serum and Subclass IgG Levels, Pneumococcal Vaccine Response, and Therapy Outcomes
Authors: Sean Kearns, Loretta Kristofek, Bill Bolgar, Luqman Seidu
Journal: Journal of Allergy and Clinical Immunology (2015)
AB0985 Comparison of two different intra-articular hyaluronic acid compounds for carpo-metacarpal joint osteoartrhitis
Authors: M. Massarotti, C. Crotti, N. Ughi, F. Uboldi, L. Belloli, B. Marasini
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Carpometacarpal osteoarthritis (CMC OA) is highly prevalent in older adults, and is often unresponsive to medical treatment. Intra-articular hyaluronic acid (HA) has been widely shown to improve pain and function in patients with knee OA and it seems to be a promising therapy also for CMC OA. To date no studies compared the efficacy of different HA compounds in CMC OA. <h3>Objectives</h3> To investigate the three-month efficacy of two different HA compounds on pain relief in CMC OA. <h3>Methods</h3> Eighty female patients affected by symptomatic CMC OA (aged 65±8 years, mean ± SD) were treated with three once-weekly intra-articular injections of HA (Hyalgan 1ml, MW 500-700 kDalton, or Jointex 1ml, MW 800-1200 kDalton). All subjects met ACR criteria for hand OA and had CMC OA grade 1-4 according to Kellgren and Lawrence on standard X-ray performed within 6 months before the inclusion. Fourty patients (aged 64±8 years, mean ± SD) were treated with Hyalgan while 40 patients (aged 67±8 years, mean ± SD) were treated with Jointex. All the patients were followed for a 3-month period after the last injection. Treatment efficacy was assessed through visual analogue scale (VAS) pain quantification (baseline; 2nd and 3rd injection; one and three months after the last injection). Side effects were recorded. <h3>Results</h3> In both groups VAS was significantly reduced after the first injection and reached the slowest score one month after the last injection (Hyalgan: 2nd injection vs baseline, p=0.0019; 3rd injection vs baseline, p&lt;0.0001; 3rd injection vs 2nd injection, p=0.057; Jointex: 2nd injection vs baseline, p=0.0008; 3rd injection vs baseline, p&lt;0.0001; 3rd injection vs 2nd injection, p=0.0096). The efficacy was maintained for all the whole follow-up period (Hyalgan and Jointex: one month vs baseline, p&lt;0.0001; three months vs baseline, p&lt;0.0001 - one month vs 3rd injection, p=n.s.;three months vs 3rd injection, p=n.s.). No significant differences in VAS score were found between the two groups at baseline and during the follow-up period (Hyalgan vs Jointex: baseline 7.05±2.33 vs 7.08±2.07; 3rd injection 4.35±2.85 vs 4.30±2.29; 1month 3.75±2.65 vs 3.25±2.22; 3months 4.23±2.90 vs 4.03±2.56; p=n.s.). Only minor side effects were observed in both treatment groups (mild pain and/or ecchymosis in injection site). <h3>Conclusions</h3> Our study supports viscosupplementation with HA as a safe and efficacious approach for symptomatic CMC OA. In our preliminary study no significant differences were found between intra-articular Hyalgan and Jointex for pain relief. Further studies are needed to determine the long-term efficacy and the optimal treatment schedule. <h3>Disclosure of Interest</h3> None Declared
Abstract 3063: Development of a sensitive COLD-PCR method for the detection of EGFR mutations in DNA
Authors: Katherine Richardson A. Richardson, Reyes Candau, Benjamin Legendre, Grant Wu, Harini Shandilya, Karissa Ekenkamp, Philip Eastlake, Gary Gerard
Journal: Cancer Research (2011)

Abstract COLD-PCR is a method to exponentially amplify mutations in DNA while linearly amplifying wild type sequences. The method can be adapted to multiple mutation detection platforms including Sanger Sequencing and is amenable to development as a diagnostic kit. EGFR EXONS 20 &amp; 21: Conditions for non-biased, selective amplification of DNA with mutations in the tyrosine kinase activation regions of the EGFR gene (exon 19 deletions and the T790M and L858R point mutations) have been developed. Ice COLD-PCR methodology was used for both exon 19 deletions and the exon 21 L858R mutation. Fast COLD-PCR methodology was used for the T790M mutation in exon 20. Using control plasmids containing the T790M and the L858R mutations, COLD-PCR amplification with SURVEYOR® Nuclease/WAVE® HS confirmation, demonstrated a limit of detection (LOD) of 0.05% mutant DNA in wild type DNA. COLD-PCR amplification followed by confirmation of these mutations using Sanger sequencing had a limit of detection of 0.2%. Only 5-10 copies of amplifiable DNA containing the mutation are needed for amplification using COLD-PCR followed by downstream mutation determination. Similar results were obtained using DNA isolated from the cell lines, H1650 and A549, and serum spiked with DNA containing a T790M mutation. EGFR EXON 19: For detection of deletions in EGFR exon 19, another series of plasmids containing 3, 6, 9, 15, and 21 base-pair deletions were constructed. The two 15 base-pair deletions were those which result in the most commonly observed mutation in non-small cell lung cancer, p.E746_A750del15 (c.2235-2249del15 or c.2236-2259del15). For these exon 19 deletions, the SURVEYOR Nuclease/WAVE HS was able to detect the presence of a mutation at 0.05% and Sanger sequencing was able to confirm these deletions at 0.2%. CONCLUSION: These data demonstrate that COLD-PCR enriches low number and low abundance EGFR mutations including point mutations and deletions, and suggests applicability to serum/plasma. COLD-PCR coupled with mutation detection methods such as Sanger sequencing is a new model for EGFR mutation testing with potential applicability for detection of mutations in other genes. 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 3063. doi:10.1158/1538-7445.AM2011-3063
Case 36-1980
Authors: Richard C. Cabot, Robert E. Scully, James J. Galdabini, Betty U. McNeely, Robert H. Rubin, John T. Fallon
Journal: New England Journal of Medicine (1980)

Presentation of CaseAn 82-year-old man was admitted to the hospital because of suspected failure of his electronic pacemaker.He was well until five years earlier, when left hemiparesis developed, and he was admitted to the hospital. On the second hospital day cardiac arrest occurred, and he was resuscitated. Persistent ventricular ectopic activity was poorly controlled by multiple medications, and a transvenous electronic pacemaker was inserted, with improvement. A permanent atrial electrode was positioned in the coronary sinus, with a programmable pacemaker set at 90 beats per minute, and the patient was discharged. Digoxin and small doses of quinidine controlled . . .
FRI0173 Reduced Hypothalamic-Pituitary-Adrenal Axis Activity in Chronic Widespread Pain: Partly Masked by Depressive and Anxiety Disorders
Authors: E. Generaal, N. Vogelzangs, G.J. Macfarlane, R. Geenen, J.H. Smit, B.W. Penninx, J. Dekker
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Results of studies on hypothalamic-pituitary-adrenal axis (HPA-axis) function amongst patients with chronic widespread pain (CWP) are equivocal and well-controlled cohort studies are rare in this field. <h3>Objectives</h3> The goal of our study was to examine whether HPA-axis function is associated with the presence and the severity of CWP. <h3>Methods</h3> Data are from the Netherlands Study of Depression and Anxiety including 1125 subjects with and without lifetime depressive and anxiety disorders. The Chronic Pain Grade questionnaire was used to determine the presence and severity of CWP. Subjects were categorized into a CWP group (n=471) and a control group (n=654). Salivary cortisol samples were collected to assess HPA-axis function (1-h awakening response, evening level, diurnal slope and post-dexamethasone level). <h3>Results</h3> In comparison with the control group, subjects with CWP showed significantly lower awakening levels and a blunted diurnal slope, in particular among those without depressive/anxiety disorders. CWP subjects with depressive and/or anxiety disorders did not show altered cortisol levels. <h3>Conclusions</h3> Our results suggest hypocortisolemia in CWP. However, if CWP is accompanied by depressive or anxiety disorder, typically related to hypercortisolemia<sup>1,2</sup>, the association between cortisol levels and CWP appears to be masked. Future studies should take psychopathology into account when examining HPA-axis function in CWP. <h3>References</h3> Knorr U, Vinberg M, Kessing LV, Wetterslev J. Salivary cortisol in depressed patients versus control persons: a systematic review and meta-analysis. Psychoneuroendocrinology35(9);1275-86,2010. Vreeburg SA, Zitman FG, van PJ, Derijk RH, Verhagen JC, van DR, Hoogendijk WJ, Smit JH, Penninx BW. Salivary cortisol levels in persons with and without different anxiety disorders. Psychosom.Med.72(4);340-7,2010. <h3>Acknowledgements</h3> This manuscript is part of the PhD programme investigating neurobiological dysregulation in chronic pain, funded through The European League Against Rheumatism (EULAR). The infrastructure for the NESDA study (www.nesda.nl) is funded through the Geestkracht program of the Netherlands Organisation for Health Research and Development (Zon-Mw, grant number 10-000-1002) and is supported by participating universities and mental health care organisations (VU University Medical Center, GGZ inGeest, Arkin, Leiden University Medical Center, GGZ Rivierduinen, University Medical Center Groningen, Lentis, GGZ Friesland, GGZ Drenthe, IQ Healthcare, Netherlands Institute for Health Services Research (NIVEL) and Netherlands Institute of Mental Health and Addiction (Trimbos)). There are no conflicts of interest. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.1497