tbuckley/cabot-search huggingface dataset:
Abstract 4751: Structure and inhibition of mitogen-activated protein kinase kinase 4 (MEK4): A prostate cancer pro-invasion protein
Authors: Sankar Narayan Krishna, Chi-Hao Luan, George Minasov, Ludmilla Shuvalova, Rebecca L. Farmer, Antoinette Nibbs, Karl A. Scheidt, Wayne F. Anderson, Raymond C. Bergan
Journal: Cancer Research (2012)

Abstract Introduction: Metastasis of Prostate Cancer (PCa) represents the second highest cause of death due to cancer among men in the United States. If this unregulated movement of cells can be inhibited, mortality arising from PCa will be greatly reduced. Our group has shown that Mitogen-activated protein kinase kinase 4 (MAP2K4/MEK4), a 399 amino acid protein, activates pro-invasion signaling pathways in human PCa. Further, we have shown that 4,5,7-trihydroxyisoavone (genistein) inhibits MEK4 kinase activity, cell invasion and metastasis of human PCa cells in a murine model. While therapeutically effective, genistein represents a non-chemically optimized natural product with additional undesired effects such as estrogenic receptor stimulation. Recognizing that MEK4 represents a novel and important therapeutic target, we have sought to characterize its structure, biochemical function and have synthesized genistein analogs designed to target it. Summary of Results: Using X-ray crystallography we have obtained a 3.38Å resolution structure of the MEK4 catalytic domain. We are in the process of improving our resolution, and of deriving 3D structures with inhibitors bound to MEK4. We have evaluated biophysical interactions between MEK4 and ligands (i.e., genistein and its analogs). Ligand binding to a protein tends to increase its stability, thereby increasing the temperature of denaturation, or melting. Using a fluorescence thermal shift (FTS) assay, we demonstrated that genistein and 6 of 39 novel analogs thermally stabilized MEK4 in a concentration dependent manner, consistent with MEK4 binding. We identified a similar pattern in 5 compounds from a commercial library, one of which was staurosporine - a broad spectrum protein kinase inhibitor. We developed and characterized a novel in vitro MEK4 kinase assay, using kinase dead p38MAPK (K53A) as substrate. In human PCa cells, MEK4 activates the p38 MAPK pro-invasion pathway. To date, we have used this assay system to demonstrate that staurosporine inhibits MEK4 with nanomolar IC50 values. Conclusions and Future Directions: MEK4 is a novel target for therapeutic intervention in PCa. Our ultimate goal is to synergistically utilize structural and biochemical information to inform the synthesis of inhibitors that specifically and selectively act upon MEK4 to inhibit human PCa metastasis in man. 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 4751. doi:1538-7445.AM2012-4751
Drainage biliaire guidé par échoendoscopie en cas d'échec ou d'impossiblité de CPRE: expérience cumulée monocentrique au terme de 101 procédures
Authors: L Poincloux, O Rouquette, D Pezet, M Dapoigny, G Bommelaer, A Abergel
Journal: Endoscopy (2015)

En cas d'échec ou d'impossibilité de CPRE, le drainage biliaire guidé par échoendoscopie (DB/EE) est une alternative au drainage biliaire percutané. Nous présentons notre expérience cumulée sur 7 ans des DB/EE pour ictère rétentionnel.
SP0011 Difficult cases: Seronegative rheumatoid arthritis
Authors: T. Sokka, D. Kyburz, T. Rannio, M. Antic
Journal: Annals of the Rheumatic Diseases (2013)

About 70% of patients with rheumatoid arthritis (RA) in any clinical cohort are seropositive.<sup>1</sup> In early RA cohorts, barely 50% are seropositive indicating that a diagnosis of RA can be established without serological markers. However, there is evidence that seropositive and seronegative RA behave differently in short term studies: van Dongen et al<sup>2</sup> showed that in anti citrulline peptide (CCP) positive patients, early MTX therapy postponed diagnosis of RA and prevented erosions statistically significantly better compared to placebo, which difference could not be seen in CCP negative patients. Few long-term studies have re-evaluated patients who have received a diagnosis of seronegative RA. In a 23-year follow-up study, Jäntti et al<sup>3;4</sup> showed that psoriatic arthritis and mild spondylarthropaties are common in these patients. Early RA is an emergency case; patients have to be treated without delay to prevent damage, functional deterioration, work disability, and other consequences of inflammatory joint diseases. As diagnosis of RA is based on consensus criteria, patients with inflammatory joint diseases that mimic early RA can be included in early RA cohorts. Only careful follow-up of patients over many years and re-evaluation of diagnosis in all patients will reveal diagnoses behind symptoms that were classified as seronegative RA. We present seronegative cases who were classified and treated as early rheumatoid arthritis and were later revealed various diagnoses. The objective of this session is to remind of the necessity to re-evaluate diagnosis of patients with persistent seronegative "RA". Sometimes wrong diagnosis may be a reason for poor response to anti rheumatic medications. <h3>References</h3> Sokka T, Kautiainen H, Pincus T, Toloza S, da Rocha Castelar PG, Lazovskis J et al. Disparities in rheumatoid arthritis disease activity according to gross domestic product in 25 countries in the QUEST-RA database. Ann Rheum Dis 2009; 68(11):1666-1672. van Dongen H, van Aken J, Lard LR, Ronday H.K, Hulsmans H.M.J., Speyer I et al. Efficacy of methotrexate treatment in patients with probable rheumatoid arthritis: A double-blind, randomized, placebo-controlled trial. Arthritis Rheum 2007; 56:1424-1432. Kaarela K, Jantti JK, Lehtinen K. Unclassified early arthritis is often spondyloarthritis. J Rheumatol 2003; 30(6):1393. Jantti JK, Kaarela K, Lehtinen KE. Seronegative oligoarthritis: a 23-year follow-up study. Clin Rheumatol 2002; 21(5):353-356. <h3>Disclosure of Interest</h3> None Declared
Stanford Scientists Ride Out Earthquake
Authors: S. Andreopoulos, L. Joyce
Journal: JNCI Journal of the National Cancer Institute (1989)

Journal Article Stanford Scientists Ride Out Earthquake Get access Spyros Andreopoulos, Spyros Andreopoulos Search for other works by this author on: Oxford Academic PubMed Google Scholar Laurel Joyce Laurel Joyce Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 81, Issue 23, 6 December 1989, Pages 1770–1771, https://doi.org/10.1093/jnci/81.23.1770 Published: 06 December 1989
Abstract 1321: ERK1/2 show different activity profiles <i>in vitro</i> and <i>in vivo</i> subsequent to NOS inhibition
Authors: Cardnell J G Robert, Ross B. Mikkelsen
Journal: Cancer Research (2010)

Abstract Nitric oxide (NO) is a crucial mediator of several survival mechanisms in tumor cells. Previous studies demonstrated that ionizing radiation (IR) stimulates NO generation activating pro-survival mechanisms including receptor tyrosine kinase and NF-κB-dependent pathways. In vitro, the IR-induced activation of these pathways survival pathways is inhibited by the NO synthase inhibitor, NG-nitro-L-arginine (L-NNA). Furthermore, the addition of L-NNA to the drinking water of flank xenograft bearing animals slows tumor progression, kills tumor cells and with radiation enhances animal survival. To elucidate the mechanism(s) by which L-NNA acts in such tumors we conducted experiments to study intracelluar signaling pathway activation by L-NNA with and without radiation. Animals bearing flank xenografts received 10 Gy whole body irradiation either with or without prior L-NNA treatment. Tumors were excised at times post IR up to 30 minutes and protein lysates prepared for analysis by western blot. Cell monolayers were also similarly treated prior to cell lysis and protein analysis. The activation (phosphorylation) of ERK1 and ERK2 was assayed in cultured monolayers and in flank xenografts using the A431 and FaDu cell lines. In vitro, the addition of L-NNA to the culture medium had little effect upon the activation of either ERK. In vivo however, L-NNA treatment up-regulated the phosphorylation of both ERK isoforms without irradiation and following irradiation elicited a significant enhancement of ERK1 phosphorylation and an inhibition of ERK2. The current consensus is that ERK1 and ERK2, due to the similarities of their protein sequence, are similarly regulated and in general activate the same substrates. However, recent evidence has emerged to indicate distinct roles for ERK1/2 in addition to their overlapping actions. Indeed, the targeting of ERK2 has been seen to abolish Ras-dependent cell proliferation, an effect not observed with ERK1 targeting. Distinct signaling roles, and the opposite effects we observe upon ERK1 and ERK2 phosphorylation in vivo following L-NNA treatment may explain our previously reported findings of enhanced tumor control. In addition, these findings my shed light upon why ERK inhibitors show only moderate efficacy in clinical trials. 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 1321.
P5-13-13: The Role of Topoisomerase IIa in Predicting Sensitivity to Anthracyclines in Breast Cancer Patients: A Meta-Analysis of Published Literatures.
Authors: J Lu, Y Du, Q Zhou, W Yin, L Zhou, G Di, Z Shen, Z Shao
Journal: Cancer Research (2011)

Abstract Topoisomerase IIα is not only a proliferation marker of tumor cells but also a target for anthracycline-based chemotherapy. Both in vitro and in vivo studies have shown that there was a relationship between topo IIα and chemosensitivity to anthracyclines, but the predictive role of topo IIα is still controversial in breast cancer patients. A meta-analysis based on published studies was performed with the aim of obtaining an accurate evaluation of the association between topo IIα and sensitivity to anthracycline-based chemotherapy. A total of 13 eligible studies including 2,633 cases and 2,118 controls were identified. Topo IIα was associated with sensitivity to anthracyclines in locally advanced breast cancer patients who received neoadjuvant chemotherapy (RR = 1.93, 95%CI: 1.27−2.94, P=0.002; RR =1.98, 95%CI: 1.37−2.86, P&amp;lt;0.001). In early breast cancer patients who received anthracycline-based adjuvant chemotherapy compared with non-taxane-based polychemotherapy, amplification(HR = 0.64, 95%CI: 0.49−0.83, P=0.001; HR = 0.59, 95% CI: 0.35−1.01, P=0.056) or deletion (HR = 0.82, 95%CI: 0.67−1.00, P=0.051; HR =0.58, 95%CI: 0.35−0.97, P=0.036) of topo IIα was significantly associated with better RFS and OS. The subgroup analysis in the early breast cancer patients indicated that taxane could be an interference for evaluation of the predictive role of topo IIα. In summary, the present meta-analysis suggests that topo IIα is a predictive factor for breast cancer patients who received anthracycline-based chemotherapy. Larger and well-designed prospective studies are required to further evaluate the predictive role of topo IIα in clinical practice. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-13-13.
Case 3-2010
Authors: Kalpathy S. Krishnamoorthy, Florian S. Eichler, Namita A. Goyal, Juan E. Small, Matija Snuderl
Journal: New England Journal of Medicine (2010)

A 4.5-month-old boy was seen in the pediatric neurology clinic of this hospital because of developmental delay and irritability. He had been born at full term to a mother who had been addicted to drugs and had hepatitis C and herpes simplex virus infections during pregnancy. Development appeared normal for the first 3 months, but at 4 months he had feeding difficulties, growth retardation, and irritability. Examination disclosed signs of spasticity. A diagnostic procedure was performed.
A1.28 Anti-carp antibodies in two large cohorts of patients with rheumatoid arthritis and their relationship to genetic risk factors and smoking
Authors: Xia Jiang, Leendert A Trouw, Tineke J van Wesemael, Jing Shi, Henrik Källberg, Vivi Malmström, Lena Israelsson, Hulda Hreggvidsdottir, Willem Verduijn, Lars Klareskog, Lars Alfredsson, Tom W J Huizinga, Rene E M Toes, Karin Lundberg, Diane van der Woude
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background and Objectives</h3> In rheumatoid arthritis (RA), the presence of antibodies to citrullinated proteins (ACPA) is strongly associated with certain genetic risk factors and smoking. The recently identified antibodies against carbamylated proteins (anti-CarP) are present in part of ACPA-positive, but also ACPA-negative RA patients. This raised the question whether the presence of anti-CarP may be associated with specific risk factors, which could provide clues about the pathogenesis of ACPA-negative RA. In this study we have therefore analysed the relationship between anti-CarP antibodies, ACPA, genetic risk factors (<i>HLA-DRB1</i> alleles and <i>PTPN22</i>) and smoking in RA. <h3>Materials and Methods</h3> Presence of antibodies to carbamylated fetal calf serum (CarP-FCS) and fibrinogen (CarP-Fib) was determined by in-house ELISAs in the Leiden Early Arthritis Cohort (EAC) and in the Swedish Epidemiological Investigation of RA (EIRA) cohort. Odds ratios for associations with different <i>HLA-DRB1</i> alleles, <i>PTPN22</i> genotypes and smoking were calculated separately for each cohort as well as in a combined meta-analysis, in RA subsets defined by anti-CarP and anti-cyclic citrullinated peptide (CCP) antibody status. <h3>Results</h3> In both cohorts,anti-CarP antibodies were mainly detected in the anti-CCP-positive population, but also in the anti-CCP-negative population. No strong associations between anti-CarP antibodies and specific <i>HLA-DRB1</i> alleles, including shared epitope alleles, could be identified, with the exception of a consistent association between anti-CarP FCS and <i>HLA-DRB1*</i>03. Further analyses did not reveal any specific associations between anti-CarP antibodies and <i>PTPN22</i> genotypes or smoking. <h3>Conclusions</h3> Anti-CarP antibodies were present in both ACPA-positive and ACPA-negative RA patients in the two separate cohorts. Except for a modest association with <i>HLA-DRB1*</i>03, there were no strong associations between anti-CarP antibodies and other <i>HLA-DRB1</i> alleles,<i> PTPN22</i> or smoking. Although it cannot be excluded that risk factors not investigated here may be importance for anti-CarP-positive disease, the lack of association found here suggests a possible fundamentally different biological mechanism for anti-CarP antibody formation compared with anti-CCP antibody formation.
COMPOUND 21, A SELECTIVE ANGIOTENSINII TYPE 2 RECEPTOR AGONIST, DOWNREGULATES LIPOPOLYSACCHARIDE-STIMULATED TISSUE FACTOR EXPRESSION IN HUMAN PERIPHERAL BLOOD MONONUCLEAR CELLS ACTIVATED BY EXPOSURE TO HIGH GLUCOSE
Authors: Cristina Balia, Valentina Scalise, Silvia Petrini, Tommaso Neri, Silvana Cianchetti, Alessandro Celi, Roberto Pedrinelli
Journal: Journal of the American College of Cardiology (2015)
Facteurs prédictifs de pancréatite aiguë post-CPRE: une étude prospective multicentrique
Authors: A Di Fiore, E Ben Soussan, M Antonietti, JF Lefebvre, I Iwanicki-Caron, F Di Fiore, P Ducrotté, S Lecleire
Journal: Endoscopy (2011)

Introduction: La pancréatite aigue est la complication la plus fréquente et la plus grave de la cholangiopancréatografie rétrograde endoscopique (CPRE) avec une fréquence allant de 2 à 20% selon les études. Actuellement, il n'existe pas de critères précis pouvant prédire la survenue d'une pancréatite aigue post-CPRE. Le but de notre étude prospective était de déterminer les facteurs prédictifs de pancréatite aigue post-CPRE.
Gene expression profiling for prediction of treatment response
Authors: J. Cossman, K. Johnson, J. Gottlieb, M. Elashoff
Journal: Journal of Clinical Oncology (2004)

9594 Background: We designed a strategy for patient stratification aimed at identifying tumor gene expression profiles that predict a favorable response to chemotherapy and allow selection of patients who would most benefit from treatment. Methods: A statistical model was developed based on global gene expression analysis of samples from 119 individuals. Two approaches were compared for their ability to disclose predictive gene expression profiles: (1) Compare normal ovary and ovarian adenocarcinoma and test that gene profile as a marker set to distinguish responsive from similarly treated, non-responsive carcinomas or (2) Directly compare gene expression profiles of responders and non-responders and apply this profile to patient samples to predict outcome. Samples were involved tissues from patients with ovarian cystadenocarcinoma obtained prior to treatment (n = 26) and histologically normal ovaries from controls (n = 93). 85% (22/26) of the ovarian carcinoma patients were advanced (Stage III-IV) disease and all were treated with paclitaxel-carboplatin. Follow-up was 6–59 months with an overall response rate of 61.5%. Gene expression was determined using Affymetrix U133 microarrays that contain >40,000 known genes and ESTs. Marker profiles were sought from pair-wise comparisons and successive validation performed by drop-replace analysis within the training sets. Results: Gene expression profiles were identified from the normal-disease comparison and were predictive of patient response to treatment. Genes can be individually weighted for their value in predicting treatment response and potentially chosen and assembled into a prognostic marker set. Conclusion: Cross-validation of the training set of 26 ovarian cancers, gives preliminary evidence that a gene set predicts outcome. The reference database of normal samples adds dimension to the building of classification models for patient disease stratification. This approach can now be compared to the predictive value of within-disease gene sets derived in the absence of normal samples. Gene expression promises to be valuable in selecting patients for clinical trials and disease management. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Gene Logic, Inc. Gene Logic, Inc. Gene Logic, Inc.
PTH-059 A Model Designed To Calculate The Cost Of Care For Inflammatory Bowel Disease (ibd).
Authors: N Ghosh, S Leonard, G Miles, P Premchand
Journal: Gut (2014)

<h3>Introduction</h3> The rising incidence of IBD, young age of onset and chronic nature mean that IBD has significant cost implications with the National IBD Audit estimating that cost to the National Health Service (NHS) exceeded £1 billion in 2010. The recent introduction of Clinical Commissioning Groups has also changed the way in which healthcare is paid for. This model is designed to be used by both commissioners and individual gastroenterology units to calculate the annual cost per patient of treating Ulcerative Colitis (UC) and Crohns Disease (CD) and to enable areas of potential cost savings to be explored. <h3>Methods</h3> The cost of care for IBD was calculated by summing the costs of treatment, treatment side effects and disease-related complications, accounting for the proportions of patients incurring these costs. Default input values for costs, the percentage of patients receiving each treatment, and the percentage of patients experiencing side effects or complications were determined from sources such as the British National Formulary (BNF), National Institute for Clinical Excellence (NICE), NHS trusts and published literature. However, an important feature of the model was its customisability allowing users to input local data, thereby generating costs which were unique and precise for that unit. <h3>Results</h3> Using default input values, the annual cost of treating any UC patient was estimated to be £3,084. For a UC patient in remission, in relapse with mild-to-moderate UC or in relapse with severe UC, annual cost per patient was estimated to be £1,693, £2,903 and £10,760, respectively. The annual cost for any CD patient was estimated to be £6,156 (£1,800 for patients in remission; £10,513 for patients in relapse). However, inputting local data would show some variability in the costs from trust to trust. Annually £743.65 was spent per UC patient on mesalazines. The model allows exploration of the cost savings if the percentage of patients on each brand of mesalazine was altered. When the percentage of relapsing CD patients on adalimumab was increased from 5% to 10%, the annual cost per relapsing CD patient rose from £10,513 to £11,032. The overall annual cost for any CD patient rose from £6,156 to £6,416. Increasing the percentage of mild-to-moderate UC patients on leukapheresis from 0.5 to 8% increased the annual cost per mild-to-moderate patient from £2,903 to £3,352, and the annual cost for any UC patient from £3,083 to £3,263. However, assuming that increased use of leukapheresis would cause a decrease from 20% to 15% in the annual proportion of patients experiencing acute severe flares, the annual cost for any UC patient fell to £3,078. <h3>Conclusion</h3> This model facilitates calculation of local annual costs per UC and CD patient, and allows areas to be identified where savings could be made. <h3>Disclosure of Interest:</h3> None Declared.