tbuckley/cabot-search huggingface dataset:
PTH-006 Effect of Medication use on Faecal Occult Blood Test Positivity in the NHS Bowel Cancer Screening Programme
Authors: M D Gill, M Bramble, C Rees
Journal: Gut (2013)

<h3>Introduction</h3> Faecal occult blood test (FOBt) positivity is linked with both tumour site and gender. Left sided cancers, and cancers in men are detected in significantly greater proportions by screening. The aim of this study was to evaluate for an association with certain medication use at time of test, with the FOBt result, in patients diagnosed with a colorectal cancer. <h3>Methods</h3> Using a regional colorectal cancer dataset (Northern Colorectal Cancer Audit Group) and Bowel Cancer Screening Programme database, all screen detected and interval cancers (diagnosed after a negative faecal occult blood test, before the next screening round) were identified. Diagnosis date was between April 2007 and March 2010. General Practitioners for each patient were asked to complete a proforma detailing use of hormone antagonists, hormone replacement therapy, anticoagulants, aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), and pre cancer diagnosis cholecystectomy. Medication use within two months of performing a FOBt was deemed positive. Chi-squared and logistic regression analyses were used. <h3>Results</h3> Of 514 patients, 346 (67.3%) proformas were returned and suitable for analysis. 120 patients analysed were in the interval cancer group, with 226 in the screen detected cancer group. Between screen detected and interval cancers groups, no difference was found in the use of hormone antagonists, hormone replacement therapy, anticoagulants, and aspirin. Rates of cholecystectomy were equivalent. The use of non-aspirin NSAIDs within two months of test was seen in a significantly greater proportion in the screen detected cancer group (10.6% vs. 4.2%, p = 0.039). For the population who used NA-NSAIDs, there was no difference between groups in gender, tumour location, or stage of tumour. <h3>Conclusion</h3> The use of NA-NSAIDs around the time of test was associated with a greater rate of positivity of the FOBt. This finding adds to our understanding of factors influencing the positivity of FOB testing, and may be useful in understanding the rates of interval colorectal cancers within the screening programme. <h3>Disclosure of Interest</h3> None Declared.
DS-04 * DOPAMINE ADDICTION IN GLIOBLASTOMA MULTIFORME DURING CHEMOTHERAPY IS MEDIATED BY A DRD2/ -ARRESTIN/AKT SIGNALING COMPLEX
Authors: L. Prestegarden, T.-C. Johannessen, A. Grudic, T. Sundstrom, H. Saed, J. Varughese, M. Lund-Johansen, R. Bjerkvig
Journal: Neuro-Oncology (2014)

Glioblastomas are highly resistant to therapy and carries a dismal prognosis. Standard of care includes surgery followed by radiotherapy (RT) with concurrent and adjuvant chemotherapy with temozolomide (TMZ). The addition of TMZ to RT increases the overall survival by approximately 3 months compared to RT alone. In this work we sought to identify synthetic lethal interactions that could potentiate TMZ treatment. By integrating results from a genome-wide lentiviral shRNA library screen with the Connectivity Map database (Broad Institute), we have identified signaling networks critical for cancer cell survival during therapy. We transfected the human GBM cell lines with a pooled RNAi library targeting approximately 5000 genes, and incubated the cells at three sub-lethal TMZ concentrations or in control medium. Individual silencing of 292 genes lead to significantly reduced cell growth in the treated population while silencing of 414 genes increased cellular viability compared to the control group. The Connectivity Map database was then interrogated using these results to identify small-molecule inhibitors that would induce analogous changes in gene expression. From this approach we identified Thioridazine, a dopamine 2-receptor (DRD2) antagonist, as a potent sensitizer for TMZ, reducing the LC50 about 20-fold. shRNA mediated downregulation of DRD2 validated these findings. Moreover, we show mechanistically that the therapeutic action of Thioridazine was mediated by autophagic cell death. Genetic and pharmacological interrogation of downstream cell signaling events identifed an activation of the DRD2/β-arrestin/Akt/mTor pathway. The therapeutic potential of Thioridazine and concomitant TMZ in vivo will be described. We believe that DRD2 represent a nodal point connecting autocrine survival cues in a subset of glioblastomas. Our findings suggest that, like androgen and estrogen dependence in prostate- and breast cancer, dopamine addiction may represent a fundamental tumor survival mechanism with important therapeutic implications.
Advanced non-small cell lung cancer (NSCLC): the prognostic role of systemic Immune-Inflammation Index (SII)
Authors: A. Savini, R. Berardi, S. Rinaldi, M. Santoni, T. Newsom-Davis, M. Tiberi, F. Morgese, M. Caramanti, M. Torniai, I. Fiordoliva, V. Paolucci, M. Bower, S. Cascinu
Journal: Annals of Oncology (2015)
Immunochemical Measurement of Elevated Levels of Gastrin in the Serum of Patients with Pancreatic Tumors of the Zollinger-Ellison Variety
Authors: James E. McGuigan, Walter L. Trudeau
Journal: New England Journal of Medicine (1968)

A radioiodine-immunoassay technic was used to measure fasting serum gastrin levels in four patients with the Zollinger-Ellison syndrome and 24 patients without gastrointestinal diseases. Serum gastrin levels in all the patients with the Zollinger-Ellison syndrome exceeded by approximately tenfold or greater the mean serum gastrin level of 425 μμg per milliliter in the control population. Gastrin was identified immunochemically in an extract derived from a pancreatic islet-cell tumor from one of the patients with the Zollinger-Ellison syndrome.
P606 THE ROLE OF TGF-β2 IN CHRONIC LIVER DISEASE (CLD) AND HEPATOCELLULAR CARCINOMA (HCC)
Authors: A. Dropmann, T. Dediulia, S. Weber, K. Abshagen, M. Wieland, S. Nittka, K. Breitkopf-Heinlein, H. Korhonen, F. Jaschinski, M. Janicot, N. Meindl-Beinker, S. Dooley
Journal: Journal of Hepatology (2014)
VEPOLOXAMER (PURIFIED POLOXAMER-188) RESTORES INTEGRITY OF CARDIOMYOCYTE CALCIUM CYCLING PROTEINS IN LEFT VENTRICULAR MYOCARDIUM OF DOGS WITH ADVANCED HEART FAILURE
Authors: Hani N. Sabbah, Ramesh C. Gupta, Vinita Sing-Gupta, Kefei Zhang, Marty Emanuele
Journal: Journal of the American College of Cardiology (2016)
The problem of selective briefings for a transparent NHS
Authors: A. C. W. May
Journal: BMJ (2013)

Spence, when defending media coverage of the NHS, overlooks the problem of selective briefings.1 These undermine public confidence in government, the media, and the NHS.

Competition among newspapers to publish exclusive stories is fierce. Front page exclusives dominate broadcast newspaper reviews, raise brand awareness, and drive sales. Newspapers depend on advertising. The Department of Health for England controls the news on health and the NHS …
FRI0418 Mortality Associated with Systemic Lupus Erythematosus in France: A Multiple Cause-Of-Death Analysis
Authors: L. Chiche, G. Thomas, B. Meunier, J. Mancini, N. Jourde-Chiche, E. Jougla, J.-R. Harle
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Systemic Lupus Erythematosus (SLE) is a chronic auto-immune disease that can be severe and life threatening. The overall mortality rate has improved significantly over the past 50 years but is still high as compared with the general population. <h3>Objectives</h3> The aim of the study is to analyze the mortality profile related to SLE in France. <h3>Methods</h3> For the 2000-2009 period, data collected in the French Epidemiological Center for the Medical Causes of Death (CépiDc, Inserm) database and corresponding to death certificates of adults (n=1593) on which SLE was listed as an underlying (n=637) or non-underlying cause (n=956) of death were analyzed using multiple cause-of-death analysis. Gender, age, sex-ratio, standardized mortality rates as well as the respective weight and frequency of the various causes of death were assessed, both at national and regional level. The observed/expected death ratio (O/E ratio) was calculated for the main causes of death. <h3>Results</h3> Mean age at death was 63.5±17.3 years. Sex-ratio was 3.5 (1238 female and 355 male). The mean standardized mortality rate was 3.2 per 10<sup>6</sup> people. For SLE as an underlying cause, the main non-underlying causes of death were cardiovascular diseases (49.5%), infectious diseases (24.5%) and renal failure (23.2%). For SLE as a non-underlying cause of death, the most common underlying causes of death were cardiovascular diseases (35.7%), neoplasms (13.9%) and infectious diseases (10.3%). The overall death O/E ratio was &gt;1 for infectious and cardiovascular diseases and renal failure (especially for people &lt;40 years of age for the 2 last causes), but was &lt;1 for neoplams. Digestive neoplasms, hematologic malignancies, and lung neoplasms were the most frequent cancers reported. Considering each type of cancer individually, an O/E ratio of &lt;1 (age and gender-adjusted) was found for lung cancer, digestive neoplasms, and gynecological neoplasms, but not for hematologic malignancies. There were no differences between the Mediterranean area and the rest of France concerning the causes of death. In overseas departments, the standardized mortality rate was higher (10.8/106 people) and the mean age of death was earlier. <h3>Conclusions</h3> For the 2000-2009 period, cardiovascular diseases are the most important cause of death associated to SLE in France with a significant excess of mortality compared to general population. It is therefore essential to improve the early identification of SLE patients at high risk for cardiovascular events in order to optimize therapeutic and preventive interventions in this population and improve survival in SLE. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.2400
Individualizing liver transplant immunosuppression using a phenotypic personalized medicine platform
Authors: Ali Zarrinpar, Dong-Keun Lee, Aleidy Silva, Nakul Datta, Theodore Kee, Calvin Eriksen, Keri Weigle, Vatche Agopian, Fady Kaldas, Douglas Farmer, Sean E. Wang, Ronald Busuttil, Chih-Ming Ho, Dean Ho
Journal: Science Translational Medicine (2016)

Posttransplant immunosuppressive drugs such as tacrolimus have narrow therapeutic ranges. Inter- and intraindividual variability in dosing requirements conventionally use physician-guided titrated drug administration, which results in frequent deviations from the target trough ranges, particularly during the critical postoperative phase. There is a clear need for personalized management of posttransplant regimens to prevent adverse events and allow the patient to be discharged sooner. We have developed the parabolic personalized dosing (PPD) platform, which is a surface represented by a second-order algebraic equation with experimentally determined coefficients of the equation being unique to each patient. PPD uses clinical data, including blood concentrations of tacrolimus--the primary phenotypic readout for immunosuppression efficacy--to calibrate these coefficients and pinpoint the optimal doses that result in the desired patient-specific response. In this pilot randomized controlled trial, we compared four transplant patients prospectively treated with tacrolimus using PPD with four control patients treated according to the standard of care (physician guidance). Using phenotype to personalize tacrolimus dosing, PPD effectively managed patients by keeping tacrolimus blood trough levels within the target ranges. In a retrospective analysis of the control patients, PPD-optimized prednisone and tacrolimus dosing improved tacrolimus trough-level management and minimized the need to recalibrate dosing after regimen changes. PPD is independent of disease mechanism and is agnostic of indication and could therefore apply beyond transplant medicine to dosing for cancer, infectious diseases, and cardiovascular medicine, where patient response is variable and requires careful adjustments through optimized inputs.
ME-20 * CULTURE OF HUMAN GBM CELLS ON ECM-MIMICKING CHITOSAN-HYALURONIC ACID SCAFFOLDS INCREASES MALIGNANCY AND DRUG RESISTANCE
Authors: K. Wang, S. Florczyk, F. Kievit, M. Zhang
Journal: Neuro-Oncology (2014)

Glioblastoma multiforme (GBM) is the most aggressive and deadly malignant primary brain tumor in humans. Development of therapeutics requires extensive screening; however, many therapeutics evaluated with 2D in vitro cultures does not translate well to similar in vivo studies and suffer from lower efficacy in patients. Replicating the in vivo tumor microenvironment in vitro with three-dimensional (3D) porous scaffolds offers the possibility of generating more predictive pre-clinical models to enhance GBM treatment efficacy. In this regard, we developed a chitosan and hyaluronic acid (C-HA) polyelectrolyte complex 3D porous scaffold to mimic the physical and chemical structure of the GBM microenvironment. C-HA scaffolds indicated a highly porous network and limited swelling. The scaffolds had a Young's modulus in the wet state that closely matches the stiffness of native brain. FTIR spectra suggested the formation of a C-HA polyelectrolyte complex due to the ionic interaction between the two polymer components. C-HA scaffold cultures promoted tumor spheroid formation and the overexpression of GBM stem cell markers. Additionally, the invasiveness of GBM cells cultured in C-HA scaffolds was significantly enhanced compared to those grown in 2D cultures as determined by the Boyden chamber invasion assay. C-HA scaffold cultures were also more resistant to temozolomide and doxorubicin, which we found was caused by increased expression of the ABCG2 drug efflux transporter. These findings suggest that C-HA scaffolds provide an in vitro platform that better mimics the in vivo GBM tumor microenvironment ECM as compared to 2D surfaces due to their 3D structure and material composition resembling the native ECM. The C-HA scaffolds demonstrated that they are a viable in vitro platform for GBM evaluation, such as screening of cancer therapeutics, and potentially for other biomedical applications.
PMO-248 Mucosal upregulation of arachidonic acid production in active ulcerative colitis: delivery of pro-inflammatory eicosanoid precursors
Authors: D S Pearl, M Masoodi, M Eiden, J Brummer, D Gullick, M A Whittaker, H Nitch-Smith, J F Brown, J K Shute, G Mills, C C Philip, T M Trebble
Journal: Gut (2012)

<h3>Introduction</h3> Ulcerative colitis (UC) is a colonic inflammatory disorder of unconfirmed aetiology. Eicosanoids, inflammatory mediators involved in UC pathogenesis, are enzymatically converted from dietary polyunsaturated fatty acids (PUFA), arachidonic acid (AA) and eicosapentaenoic acid (EPA), themselves competitive substrates also generated via a fatty acid (FA) biosynthetic cascade. Dietary studies using fish oil-derived EPA have been disappointing in UC; we hypothesised that the PUFA biosynthetic pathway in inflamed tissue is altered. This study evaluated PUFA profile in inflamed and non-inflamed mucosa from UC patients and compared to matched controls. <h3>Methods</h3> Ethical approval was obtained. Patients were prospectively recruited from outpatients9 clinics. Mucosal biopsies at flexible sigmoidoscopy (FS) were taken from UC patients within inflamed and normal proximal mucosa. Age-sex matched control patients undergoing FS for functional symptoms were compared. Inflammation was scored endoscopically and histologically. Membrane bound FA (MBFA): Biopsies were spiked with deuterated internal standard, followed by liquid-liquid extraction and quantitative gas chromatography mass spectrometry (MS). Free Fatty Acid (FFA): Biopsies were homogenised, followed by solid phase extraction and liquid chromatography orbitrap MS. Data were expressed as percentage abundance. Dietary fatty acid analysis was undertaken. Wilcoxon signed rank pair and Spearman9s correlation analysis were employed. <h3>Results</h3> 69 active UC patients (54 paired normal/inflamed mucosa) and 69 controls were compared. No biologically significant differences were noted between endoscopically normal mucosa from UC patients and controls other than DPA (p&lt;0.0025). Inflamed mucosa compared to non-inflamed mucosa demonstrated highly significant reduction in LA and αLNA (p&lt;0.0001) and increased AA, DPA, and DHA (p&lt;0.0001); EPA was reduced (p&lt;0.005). The ratio of AA/EPA was increased in inflamed mucosa (p&lt;0.0001). These findings are consistent between MBFA and FFA and correlate with severity of inflammation. <h3>Conclusion</h3> Mucosal PUFA bioavailability is altered in active UC, with significant elevation of AA and reduction of LA, αLNA and EPA. This suggests modification of the FA biosynthetic pathway with elevated delivery of AA as a precursor of pro-inflammatory eicosanoids in active UC. These findings may explain the lack of efficacy of supplemental fish oil and suggests new alternative therapeutic targets. <h3>Competing interests</h3> None declared.
Abstract 3378: HO-1 challenges the epithelial mesenchymal transition in prostate cancer
Authors: Geraldine Gueron, Angeles Salles, Estefania Labanca, Federico Coluccio, Nora Navone, Adriana De Siervi, Elba Vazquez
Journal: Cancer Research (2011)

Abstract Prostate cancer (PCa) is the second leading cause of cancer-associated death in men. Tumorigenesis is highly associated with inflammation. Key mediators of this event may play multiple roles in the etiology of PCa and the onset of its progression. The metastatic spread of PCa cells relies on their ability to undergo EMT acquiring undifferentiated properties, loosing the tight junctions between them, hence becoming more motile and invasive. In this context, heme oxygenase-1 (HO-1), the inducible isoform of the rate-limiting enzyme in heme degradation, emerges as a potential epithelial mesenchymal transition (EMT) modulator counteracting oxidative and inflammatory damage. Here we assessed the expression profile of the EMT markers and the interplay between EMT regulators in androgen sensitive (MDAPCa2b and LNCaP) and insensitive (PC3) PCa cell lines under HO-1 modulation. Our results show that treatment with hemin, a potent and specific inducer of HO-1, increased mRNA levels of E-cadherin, β-catenin, and endoglin. Stable transfection of HO-1 in PC3 (PC3HO-1) also showed a significant increase of these epithelial markers. PC3HO-1 xenografts growing subcutaneously in athymic nude mice showed significant up-regulation of these markers compared to control tumours. Furthermore, using an RT-qPCR-generated gene array we identified the adhesion molecule COL4A3 as a novel downstream target of HO-1. HO-1 modulation limited the metastatic potential of neoplastic cells by up-regulating COL4A3 production. Moreover, a quantitative analysis of cell adhesive forces revealed that HO-1 induction increased PCa cell adhesion to a collagen IV matrix. Taken together these results implicate for the first time HO-1 in the modulation of the EMT and cell adhesion in PCa progression. Targeting EMT program directly or indirectly through HO-1 modulation may represent a novel avenue to decrease tumor bulk and eradicate undifferentiated cells with potential to colonize a rare field. 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 3378. doi:10.1158/1538-7445.AM2011-3378
Case 15-2004
Authors: Karen K. Ballen, Robert P. Hasserjian
Journal: New England Journal of Medicine (2004)

A 31-year-old man noted fluctuating, painless testicular enlargement over a period of two months. There was no evidence of feminization, and the levels of the β subunit of human chorionic gonadotropin and alpha-fetoprotein were normal. The discussants review the differential diagnosis of testicular enlargement in a young adult, the diagnostic testing needed to establish a diagnosis, and the treatment of the unusual lesion that was ultimately diagnosed.
COMPARISON OF TWO SUTURE MEDIATED CLOSURE DEVICES FOR ACCESS SITE CLOSURE AFTER TRANSFEMORAL AORTIC VALVE IMPLANTATION
Authors: David Jochheim, Mohamed Abdel-Wahab, Moritz Baquet, Magda Zadrozny, Mohamed El-Mawardy, Philipp Lange, Christian Kupatt, Hans Theiss, Martin Greif, Joerg Hausleiter, Axel Bauer, Gert Richardt, Steffen Massberg, Julinda Mehilli
Journal: Journal of the American College of Cardiology (2015)
FRI0491 Possible Role of Iloprost in Vivo on T-Lymphocyte Regulation Pathway in Early Systemic Sclerosis (ESSC)
Authors: P. Faggioli, A. Gatti, A. Mazzone, A. Sciascera, A.G. Gilardi, B. Brando
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Systemic Sclerosis (SSc) is an autoimmune disease characterized by fibrosis and vasculopathy. In patients with active SSc increasing values of the Th17 subset and of pro-fibrotic interleukins such as IL6, IL1 and IL17 were demonstrated, as compared to healthy controls. Iloprost, a stable prostacyclin analogue, has been shown to down regulate pro-inflammatory cytokines, but its role on T cells modulation is not completely understood <h3>Objectives</h3> To evaluate functional T cells subsets in patients with early SSc (eSSc) in basal conditions and after Iloprost treatment <h3>Patients and Methods</h3> A total of 7 previously untreated female patients with eSSC (mean age 41.7 years) were enrolled in this study. Two patients were positive for anti-scl70 autoantibodies and five for anti-centromer antibodies, with a mean skin score of 12 (nobody presented digital ulcers) and Medseger score of 5.1 (range 4.8 – 6.7). All patients were treated with i.v. Iloprost (0.3ng/kg for 6 hours in continuous infusion for 5 days). The analysis of T cells subsets, including Th1, TH2, Th17, quiescent CD8 (CD8+/CD38-/HLADR-) and activated CD8 (CD8+/CD38+/HLADR+) was carried out on peripheral blood samples by 8-color flow cytometry. Patients were studied first in basal condition and after 5 days of therapy. Fifteen healthy subjects were studied as controls. <h3>Results</h3> Our results shown: a) Low basal absolute values of CD4+T cells in patients with eSSc (mean 776.5/mL, range 424.8/mL-1520.4/mL) vs control group (mean 1048.1/mL, range 642/mL -1683/mL); b) Lower values of percent and absolute CD4+TH17+ cells in the eSSc group, mean 7.66% vs 12.59% (range 4.2% - 12.1% vs 2.7% - 20.3%, p&lt;0.05) and mean 53.92/mL vs 123.1/mL (range 26.34/mL – 87.47/mL vs 45.44/mL-257.8/mL, p&lt;0.05), respectively; c) Reduced baseline quiescent CD8+T cells values and increased activated CD8+T cells after treatment (baseline mean quiescent CD8+ cells: 86.71% and 494.7/mL vs post therapy mean CD8+ cells: 74.54% and 478.3/mL, basal activated CD8+ cells: 1.86% and 13.4/mL vs after treatment activated CD8+ cells: 2.41% and 18/mL), respectively <h3>Conclusions</h3> The literature data on T cell regulatory subsets in eSSc are scanty. Our approach included the phenotypic evaluation of CD4+Th17+ cells using CCR6 and CXCR3, so that our measured levels may be higher than those using direct intracellular IL17 evaluation. The low baseline level of CD4+Th17+ cells may be related to the very early phase of the disease, whereas the increase in activated CD8+ cells can be related to the anti-inflammatory and anti-fibrotic effects of Iloprost <h3>References</h3> Truchetet ME et al. Ann Rheum Dis 2012; 71: 2044-2050. Liu W et al. Prostaglandins Leukot Essent Fatty Acids 2013; 89: 335-344. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.5774