tbuckley/cabot-search huggingface dataset:
Abstract 717: JAK2/STAT3 induces erlotinib-resistance in lung cancer cells harboring EGFR-activating mutations
Authors: Daijiro Harada, Daijiro Harada, Nagio Takigawa, Kadoaki Ohashi, Eiki Ichihara, Toshio Kubo, Hiromasa Takeda, Hiromi Kashihara, Katsuyuki Hotta, Mitsune Tanimoto, Katsuyuki Kiura
Journal: Cancer Research (2011)

Abstract Epidermal growth factor receptor (EGFR) inhibitors, including the small molecule tyrosine kinase inhibitors such as gefitinib and erlotinib, have demonstrated promising effects in non-small cell lung cancer harboring EGFR-activating mutation. But even in the patients with an initial dramatic response, acquired resistance to the EGFR tyrosine kinase inhibitor develops almost without exception after varying periods of time, usually 6-12 months. Secondary mutations such as T790M mutation in EGFR and/or amplification of the gene encoding the MET receptor tyrosine kinase account for some of the resistance. However, tumors from approximately 40% of patients with acquired resistance do not have the known mechanisms. We generated an erlotinib-resistant cell line (PC-9/ER3) from PC-9 that harbored the delE746-A750 mutation, by exposing the cell line to erlotinib for 12 weeks. The cytotoxicity of the drugs for the cells was evaluated using MTT assay. The drug concentration required to inhibit the growth of tumor cells by 50% (IC50) for 96 h exposure was used to evaluate the cytotoxicity. Protein expression was determined by Western blotting. The PC-9/ER3 cells were 250-fold more resistant to erlotinib than the parental cells, and were stable for 20 weeks or longer without erlotinib exposure. The resistant cells harbored neither T790M mutation nor MET gene amplification. Erlotinib suppressed pEGFR and pMAPK, however, increased pSTAT3 in both PC-9 and PC-9/ER3 cells. No differences were observed in the IC50 values of JSI-124, a JAK2 inhibitor that suppresses STAT3 phosphorylation, between the parental and resistant cells. The PC-9/ER3 cells restored sensitivity to erlotinib when combined with JSI-124 (0.05 µM), even though the IC50 values of erlotinib combined with JSI-124 in the PC-9 cells did not change. Additionally, pSTAT3 increased by erlotinib was suppressed by JSI-124 both in the PC-9 and PC-9/ER3 cells. pAKT expressions treated by erlotinib with or without JSI-124 seemed to be equivalent in the PC-9 cells; however, the combination of erlotinib with JSI-124 more suppressed pAKT compared to erlotinib alone in the PC-9/ER3 cells. Our results would suggest that the activation of JAK2/STAT3 signaling pathway followed by continuous erlotinib exposure accounts partly for the acquired resistance, and that it might be overcome by the combined treatment with JAK2 inhibitor. 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 717. doi:10.1158/1538-7445.AM2011-717
Receptor activator of NF-kB (RANK) and RANK ligand protein expression in invasive ductal carcinoma.
Authors: M Roudier-Meyer, A Jacob, M Tometsko, R Erwert, L Woody, R Soriano, L Huang, J Hawkins, D Branstetter, W Dougall
Journal: Cancer Research (2009)

Abstract Abstract #2057 Purpose: Bone metastases are commonly observed in patients with advanced breast cancer. Tumor cells interact with the bone microenvironment to induce osteoclastogenesis via local bone stromal expression of receptor activator of NF-kB ligand (RANKL), leading to bone destruction and release of growth factors. In addition to its critical role in tumor-induced osteolysis, RANKL has been demonstrated to enhance the invasive behavior of epithelial tumor cells that express RANK, and RANK over-expression in transgenic mice using the breast-specific MMTV promoter results in increased mammary carcinoma. This study assessed the expression of human RANK and its ligand (RANKL) in invasive ductal carcinoma (IDC).&amp;#x2028; Methods: We studied a total of 57 IDC specimens. Antibodies against human RANK (AF683) and human RANKL (M366; Amgen) were used for immunohistochemistry (IHC) cell staining along with an isotype control. The specificity of the 2 antibodies was substantiated by IHC, flow cytometry and Western blot analysis of positive and negative control cells. In addition, for RANK, mass spectrometry/protein sequencing of immunoprecipitated proteins was performed. The intensity of IHC staining was scored on a semiquantitative scale (1=weak, 2=moderate, 3=intense) or a complex scale (sum of percentages of stained tumor cells x staining intensity (0-3)).&amp;#x2028; Results: Using a complex score with a threshold of 10, 20/57 IDC (35%) expressed minimal level of RANK (range 0 to &amp;lt;10, median 1) while 37/57 IDC (65%) expressed RANK protein with a score ranging from 10 to 100 (median 50). The expression in the tumor was heterogeneous, with cells having no expression and cells having intense expression. In addition, RANK was intensely expressed in the basal layer of all normal ducts and lobules. RANKL was observed in rare tumors (7/57; 11%), in rare lymphocytes of most tumor stroma (42/62; 68%), and in rare fibroblast-like cells in the stroma of rare tumors (3/62; 4.8%).&amp;#x2028; Conclusion: In this study, RANK expression was observed by IHC in the majority (65%) of IDC. RANKL expression was observed in the epithelial carcinoma element of some tumors (11%) and was detected in 68% of tumors in rare lymphocytes infiltrating the tumor stroma. Correlation studies between prognosis markers ER, PR, Her2, and CK5/6 expression and RANK or RANKL expression in those IDC have been initiated. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2057.
ENTEROSCOPIA DE UN SOLO BALÓN: EFICACIA Y SEGURIDAD EN EL ESTUDIO DE ENFERMEDADES DEL INTESTINO DELGADO
Authors: V Prieto Vicente, A Fernández Pordomingo, A Álvarez Delgado, A Velasco Guardado, AB Prieto Bermejo, A Sánchez Garrido, A Rodríguez Pérez
Journal: Endoscopy (2010)

Introducción: Evaluar las indicaciones, el impacto clínico y la seguridad de la enteroscopia de un solo balón (ESB) en el estudio de la patología del intestino delgado.
The German colonoscopy screening program: the quality of a quality register
Authors: Geir Hoff
Journal: Endoscopy (2013)

Colorectal cancer (CRC) is a worldwide health issue with 1.2 million new cases annually and a 5-year survival rate of approximately 50 %. Symptoms are unspecific and often appear late in its clinical course; however, only early diagnosis with surgery offers the prospect of being cured. Therefore, the European Union has recommended CRC screening programs for its member states since 2003, provided that adequate quality assurance programs are also implemented. This is in line with leading authorities on quality assurance in general, which state that “policy makers in research should reliably set aside a budget for research on quality and safety of care and implementation of change whenever they examine a new, relevant, clinical care topic” [1].
A2.28 Prevalence of antibodies to glycoprotein 2 in patients with spondyloarthropathies
Authors: M Volkava, E Kundzer, I Generalov, D Petrovich
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background and objectives</h3> Autoimmune diseases are characterised by tissue damage and loss of function due to an immune response that is directed against specific organs. Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to non-self antigens. Pancreatic zymogen granule protein 2 Glycoprotein 2 (GP2) has been identified as a major autoantigenic target of the so-called pancreatic antibodies. Antibodies to GP2 have demonstrated diagnostic significance for Crohn's disease. Anti-GP2 autoantibodies are detected in 25–30% of patients with CD and in 5–12% of patients with UC. There are certain relationships in pathgenesis and clinical course of inflammatory bowel diseases and spondyloarthropathies. The aim of our study is to investigate the prevalence of anti-GP2 in patients with SpA and evaluate the potential impact in relationships between gut inflammation and development the systemic autoimmune process. <h3>Materials and methods</h3> We studied 87 patients with SpA (64 patients with ankylosing spondylitis (AS), 23 – with psoriatic arthritis (PsA). As healthy controls 160 adult blood donors were included. All patients are fulfilled respective latest classification criteria. Levels of anti-GP2 antibodies (IgA and IgG classes) have been detected by ELISA, employing recombinant human GP2 (Medipan GmbH, Germany). Cut-off levels, determined by manufactures, are ≥20 U/ml. <h3>Results</h3> Anti-GP2 IgA were more prevalent in SpA (39/87, 44.82%) in controls (6/160, 3.75%) (p &lt; 0.001). PsA patients did not reveal a significant prevalence prevalence of anti-GP2 IgA (13/23, 56.52%) in comparison with AS patients (26/64, 40.65%, p = 0.3). Anti-GP2 IgG were more prevalent in SpA (17/87, 19.54%) patients than in controls (4/160, 2.5%) (p &lt; 0.001). PsA patients showed a significantly higher prevalence of anti-GP2 IgG (9/23, 37.5%) in comparison with AS patients (8/64, 12.5%, p = 0.019). <h3>Conclusions</h3> Anti-GP2 antibodies, considering as a novel CD-specific markers, are found to be positive in about 44% of patients with SpA. Moreover, the highest prevalence anti-GP2 IgA was observed in PsA patients. These data may help to find new interrelationships between gut inflammation and the development of autoimmune diseases.
A5.9 Sphingosine-1-phosphate counteracts interleukin-1β in human chondrocytes.
Authors: Martin H Stradner, Gerald Gruber, Hannes Angerer, Verena Huber, Daniela Setznagl, Marie-Luise Kremser, Florentine C Fürst, Reinhard Windhager, Winfried B Graninger
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background and Objectives</h3> The lipid mediator Sphingosine-1-phosphate (S1P) is found in the synovial fluid of osteoarthritis (OA) patients. S1P protects bovine cartilage by counteracting interleukin-1β (IL-1β). Here we examine the interaction of S1P and IL-1β in human OA chondrocytes. <h3>Materials and Methods</h3> Human cartilage was obtained from patients undergoing total knee joint replacement. Chondrocytes were cultured in monolayer and treated with IL-1β and S1P. Expression of S1P receptor sub-types and genes involved in cartilage degradation was evaluated using real-time PCR, immunohistochemistry and western blot. S1P signalling was evaluated using inhibitors of S1P receptors and siRNA knock-down of the S1P<sub>2</sub> receptor. Phosphorylation of MAP kinases (MAPK) and NF-κB in response to IL-1β and S1P was detected by western blot. <h3>Results</h3> S1P<sub>2</sub> was the most prevalent S1P receptor subtype in human OA cartilage and chondrocytes in vitro. S1P reduced iNOS expression in IL-1β treated chondrocytes. Reduction of ADAMTS4 and MMP-13 expression by S1P correlated with S1P<sub>2</sub> expression. Pharmacological inhibition of the S1P<sub>2</sub> receptor but not S1P<sub>1</sub> and S1P<sub>3</sub> receptors abrogated inhibition of iNOS expression. Similar results were observed using siRNA knock-down. S1P signalling inhibited IL-1β induced phosphorylation of p38<sup>MAPK</sup>. <h3>Conclusions</h3> In human chondrocytes, S1P reduces the induction of catabolic genes in the presence of IL-1b. Activation of the S1P<sub>2</sub> receptor counteracts the detrimental phosphorylation of p38<sup>MAPK</sup> by IL-1β.
PM-02 * CONDITIONAL INACTIVATION OF SMARCB1 IN P0 PERMISSIVE MOUSE CELLS GENERATES RHABDOID TUMORS IN THE PERIPHERAL NERVOUS SYSTEM AND IN THE BRAIN
Authors: J. Vitte, F. Chareyre, A. Stemmer-Rachamimov, A. Judkins, M. Giovannini
Journal: Neuro-Oncology (2015)

Inactivation of the SMARCB1/Snf5/Ini1 tumor-suppressor gene was originally described as a hallmark of malignant rhabdoid tumors (MRT), an aggressive tumor of early childhood. Recently, SMARCB1 germline mutations have been found in patients with familial or sporadic schwannomatosis, which is characterized by the onset of multiple schwannomas, benign tumors occurring during adolescence and adulthood. The mechanisms by which SMARCB1 germline mutations predispose to schwannomatosis versus MRT are still unknown. Schwannomas are benign neoplasms of the peripheral nerve sheath and are believed to have their origin in embryonic neural crest cells. We used conditional mutagenesis to investigate the role of Smarcb1 biallelic inactivation in mouse neural crest and Schwann cell lineage. In this model, Cre recombinase expression was under the control of the protein zero (P0) gene promoter. P0Cre;Smarcb1flox/flox mice showed reduced viability and at 5 months of age most of the mice presented tumors arising from different cranial nerves (olfactory, trigeminal, vestibulocochlear) or developing in the brain. Brain tumors were mostly found very close to or in contact with the meninges of the rostral part of the cortex leading to the hypothesis that these tumors would arise from the cranial neural crest cell-derived meninges. Analysis of the tumors demonstrated typical histological features of rhabdoid tumors with a histologic spectrum from a primitive neuroectodermal pattern to a more differentiated mesenchymal pattern with extensive spindle shape cell differentiation. Typical rhabdoid cells were found isolated or in nest in most of the tumors. Molecular analysis of the tumors showed derepression of cyclin D1 as found in mouse and human MRT. Altogether, our data not only establish a new model of Smarcb1-related tumorigenesis, but also provide important insight into the cell of origin of MRT.
Abstract 1844: CD43 normally expressed on the surface of leukocytes is expressed in the cytoplasm and nucleus of breast cancer and is a novel therapeutic target
Authors: Carl S. Shelley, Qiangwei Fu, Steven E. Cash, Jeremiah J. Andersen, Colin R. Kennedy, Leah L. Dietrich, William A. Agger
Journal: Cancer Research (2012)

Abstract One in eight of the female population of the United States will be diagnosed with breast cancer in their lifetime. This statistic defines breast cancer as the most common cancer affecting American women. Advances in breast cancer treatment will be facilitated by the identification and targeting of the causative molecular defects. We have found that breast cancer is characterized by expression of CD43. This sialoglycoprotein is normally only produced by leukocytes. Strikingly, an N-terminal domain of CD43 that is extracellular in leukocytes is expressed predominantly in the cytoplasm of breast cancers. The C-terminal domain that is expressed in the nucleus of leukocytes only upon activation exhibits constitutive nuclear localization in breast cancer. Segregation of the N and C terminal domains of CD43 between different subcelluar compartments suggests that in breast cancer it is subjected to specific proteolytic cleavage events. The normal function of CD43 is to regulate leukocyte adhesion, apoptosis and migration. We reasoned that if these normal functions are extrapolated to breast cancer, then CD43 could contribute to disease progression and, therefore, represent a novel therapeutic target. We tested this hypothesis by using small-interfering RNA to target CD43 expressed by the breast cancer cell line MCF7. This targeting resulted in cancer cells exhibiting increased susceptibility to apoptosis and increased vulnerability to lysis by natural killer cells. In addition, targeting demonstrated that CD43 likely facilitates metastasis by inhibiting homotypic adhesion and driving transendothelial migration. Using an othrotopic mouse model, we demonstrate that CD43-targeting reduces the size of primary tumors by 76%. Taken together, our results indicate that expression of CD43 is a robust breast cancer biomarker and its targeting has the potential to be developed into a new breast cancer therapy. 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 1844. doi:1538-7445.AM2012-1844
Abstract 5380: Disulfiram sensitised cytotoxicity of gemcitabine in human glioblastoma cell lines
Authors: Sarah Brown, Peng Liu, Tuge Goktug, John Darling, Weiguang Wang
Journal: Cancer Research (2010)

Abstract The blood and brain barrier (BBB) and chemoresistance are the major obstacles for the success of glioblastoma multiforme (GBM) chemotherapy. It has been shown that high nuclear factor kappa B (NFκB) activity is highly related to chemoresistance. Gemcitabine (dFdC) can easily cross the BBB and gets into GBM tissues. Due to the chemoresistance of GBM cells to dFdC induced cytotoxicity, this drug is currently only used as a radiosensitiser for GBM treatment. Disulfiram (DS) is an anti-alcoholism medicine. Our previous study demonstrates that DS strongly inhibits NFκB activity and sensitises cancer cell lines to several anticancer drugs including dFdC. DS can freely pass through BBB. Therefore, we tested the chemosensitising effect of DS on dFdC in three GBM cell lines (U251MG, U87MG and U373MG). DS was cytotoxic to GBM cell lines. Copper (Cu) was essential for DS induced cytotoxicity in GBM cell lines. Cu or DS alone was not cytotoxic to GBM cell lines in vitro. Whereas high cytotoxicity (IC50 = 150 - 250 nM) was demonstrated when DS was dosed in combination with physiological concentration of Cu (1 µM). We also tested the chemosensitising effect of DS/Cu complex on dFdC in GBM cell lines. The GBM cell lines were highly resistant to dFdC induced cell death. DS significantly sensitised the cytotoxicity of dFdC in GBM cell lines (∼ 6 - 23-fold; Table 1). CI-isobologram analysis indicated that the combination effect between DS/Cu and dFdC was highly synergistic (Table 1). Flow cytometric data demonstrated that DS/Cu enhanced dFdC induced apoptosis. The molecular chemosensitising mechanisms of DS/Cu to dFdC in GBM cells are still not full elucidated. Our preliminary data indicated that DS/Cu simultaneously inhibited NFκB pathway and triggered reactive oxygen species (ROS)-JNK pathway.Cytotoxicity of dFdC alone or dFdC plus DS/Cu in GBM cell lines U251MGU87MGU373MGdFdC alone100.4 (22.3)&amp;gt;40078.6 (5.6)dFdC + DS/Cu (1:10 ratio)17.5 (5.1)17.1 (3.0)6.8 (1.8)CI0.390.470.82 Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. 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 5380.
Abstract 2092: Pathway specific gene profiling analysis reveals potential target genes of the stress oncoprotein LEDGF/p75 in prostate cancer cells
Authors: Anamika Basu, Awa Drame, Marino De Leon, Carlos A. Casiano
Journal: Cancer Research (2011)

Abstract Chronic inflammation in the prostate microenvironment, with its associated increase in oxidative stress, is critical for prostate carcinogenesis since it leads to DNA mutations and epigenetic changes, as well as deregulation of stress and antioxidant proteins that protect prostate cells against oxidative damage and cell death. The lens epithelium-derived growth factor p75 (LEDGF/p75), an oxidative stress-induced transcription coactivator, is overexpressed in prostate tumors and other tumor types. LEDGF/p75 is emerging as a stress oncoprotein that protects cancer cells against lysosomal cell death and promotes resistance to chemotherapeutic drugs. We hypothesize that the pro-survival function of LEDGF/p75 is associated with its ability to promote the transcriptional activation of protective stress genes. To date, only very few candidate target genes of LEDGF/p75 have been identified in cancer cells. Towards this goal we initiated a stress focused gene profiling analysis of PC3 prostate cancer cells overexpressing or lacking LEDGF/p75, using the Real Time PCR Array System (SABiosciences). We selected an array that contained 80 genes involved in the cellular stress response and antioxidant defense. siRNA oligos targeting the C-terminus of the LEDGF/p75 mRNA sequence were used to induce transient LEDGF/p75 knockdown in PC3 cell. LEDGF/p75 was also stably overexpressed in PC3 cells by transduction with a lentiliviral vector. Both transient siRNA-mediated knockdown and overexpression of LEDGF/p75 were associated with significant changes in the expression of several stress/antioxidant genes, using a cutoff fold change value of 1.5 (P&amp;lt;0.001). We selected for further analysis common genes that were significantly downregulated when LEDGF/p75 was knocked down and upregulated when this protein was overexpressed. These genes are phosphoinositide-binding protein E, cytoglobulin, superoxide dismutase 3, thyroid peroxidase, titin, glutathione transferase zeta1 and albumin. The expression of these genes in response to LEDGF/p75 expression was further validated using real-time RT-PCR. This study identifies candidate stress genes potentially regulated by LEDGF/p75 in PC3 cells, and provides a rationale for investigating the mechanisms by which this emerging stress oncoprotein promotes resistance to lysosomal cell death and chemotherapy in prostate tumor cells. 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 2092. doi:10.1158/1538-7445.AM2011-2092
A Molecular Defect in the Vasopressin V2-Receptor Gene Causing Nephrogenic Diabetes Insipidus
Authors: Eliezer J. Holtzman, H. William Harris, Lee F. Kolakowski, Lisa M. Guay-Woodford, Barbara Botelho, Dennis A. Ausiello
Journal: New England Journal of Medicine (1993)

Fundamental to the maintenance of water balance in humans is the rate at which the kidneys excrete free water, which is primarily regulated by arginine vasopressin. The antidiuretic action of argin...