tbuckley/cabot-search huggingface dataset:
Abstract PL02-02: Lgr5 ctem cells in self-renewal and cancer
Authors: Hans Clevers
Journal: Cancer Research (2012)

Abstract The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. We originally defined Lgr5 as a Wnt target gene, transcribed in colon cancer cells. Two knock-in alleles revealed exclusive expression of Lgr5 in cycling, columnar cells at the crypt base. Using an inducible Cre knock-in allele and the Rosa26-LacZ reporter strain, lineage tracing experiments were performed in adult mice. The Lgr5+ve crypt base columnar cells (CBC) generated all epithelial lineages throughout life, implying that it represents the stem cell of the small intestine and colon. Similar obserations were made in hair follicles and stomach epithelium. Single sorted Lgr5+ve stem cells can initiate ever-expanding crypt-villus organoids in 3D culture. Tracing experiments indicate that the Lgr5+ve stem cell hierarchy is maintained in these organoids. We conclude that intestinal crypt-villus units are self-organizing structures, which can be built from a single stem cell in the absence of a non-epithelial cellular niche. The same technology has now been developed for the Lgr5+ve stomach stem cells. Intestinal cancer is initiated by Wnt pathway-activating mutations in genes such as APC. As in most cancers, the cell of origin has remained elusive. Deletion of APC in stem cells, but not in other crypt cells results in progressively growing neoplasia, identifying the stem cell as the cell-of-origin of adenomas. Moreover, a stem cell/progenitor cell hierarchy is maintained in early stem cell-derived adenomas, lending support to the “cancer stem cell”-concept. Fate mapping of individual crypt stem cells using a multicolor Cre-reporter revealed that, as a population, Lgr5 stem cells persist life-long, yet crypts drift toward clonality within a period of 1-6 months. Lgr5 cell divisions occur symmetrically. The cellular dynamics are consistent with a model in which the resident stem cells double their numbers each day and stochastically adopt stem or TA fates after cell division. Lgr5 stem cells are interspersed between terminally differentiated Paneth cells that are known to produce bactericidal products. We find that Paneth cells are CD24+ and express EGF, TGF-a, Wnt3 and the Notch ligand Dll4, all essential signals for stem-cell maintenance in culture. Co-culturing of sorted stem cells with Paneth cells dramatically improves organoid formation. This Paneth cell requirement can be substituted by a pulse of exogenous Wnt. Genetic removal of Paneth cells in vivo results in the concomitantloss of Lgr5 stem cells. In colon crypts, CD24+ cells residing between Lgr5 stem cells may represent the Paneth cell equivalents. We conclude that Lgr5 stem cells compete for essential niche signals provided by a specialized daughter cell, the Paneth cell. 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 PL02-02. doi:1538-7445.AM2012-PL02-02
Nonsyphilitic Interstitial Keratitis and Bilateral Deafness (Cogan's Syndrome) Associated with Cardiovascular Disease
Authors: Bernard Eisenstein, Matthew Taubenhaus
Journal: New England Journal of Medicine (1958)

NONSYPHILITIC interstitial keratitis with vestibuloauditory symptoms was first recognized as a clinical entity by Cogan1 , 2 in 1945. This syndrome usually occurs in young adults and is of sudden onset, initiating with either the ocular or the aural manifestations. The symptoms of both systems may occur almost simultaneously or may be delayed for several months, but usually appear within a few weeks of each other. The vestibuloauditory symptoms are similar to those seen in Ménière's syndrome and consist of sudden onset of vertigo, tinnitus, nausea, vomiting and rapid development of deafness. With the appearance of deafness, which is often complete, the . . .
Abstract 384: Effects of endostar on cell functions and biological characteristics in tumor-derived endothelial cells
Authors: Yong He, Li Jiang
Journal: Cancer Research (2010)

Abstract Tumor microvessels are essential to tumor formation, growth, and metastasis. Interventions targeting the microvessels would lead to avascular necrosis of tumor cells. Therefore, specifically targeting endothelial cells in tumor vasculature had become one of the most important strategies for cancer therapy. Endostar, a novel recombinant human endostatin with an additional nine-amino acid sequence, is a novel anti-angiogenesis drug. This present study is to determine how endostar affects the behavior of endothelial cells and tumor-derived endothelial cells both in vitro and in vivo. Human umbilical vein endothelial cells (HUVEC) were cultured and differentiated to tumor-derived endothelial cells (Td-ECs) after co-culturing with conditioned medium from A549 cells, a lung cancer cell line. The anti-angiogenesis effects of endostar on Td-ECs were examined by MTT assay, cell migration assay, flow cytometry, and TUNEL assay. Endostar exhibited a significant inhibitory effect both time and dose dependently in Td-EC cells. In addition, Endostar significantly inhibited cell migration and induced G0/G1 and S phase cell cycle arrest and apoptosis. However, under the same concentrations, Endostar has little impact on HUVEC. To study the in vivo effects, a xenograft model in nude mice was established. Endostar was injected intratumorally as localized administration, and tumor growth was closely monitored during the following days. As a result, endostar showed significant anti-angiogenesis effect and tumor growth inhibition. The concentration of Ca2+ in the treatment groups measured by fluorescence spectrometry was elevated significantly compared to that in the control group. This study revealed a novel activity of endostar in inhibiting angiogenesis, more potently in tumor-derived endothelial cells than in normal endothelial cells. This finding suggests the potential use of endostar as cancer therapeutic to be tested in clinical trials. 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 384.
Abstract P4-09-06: miR-187 is an independent prognostic factor in lymph node-positive breast cancer patients.
Authors: DP O'Connor, L Mulrane, DJ Brennan, S Madden, G Gremel, SF McGee, S McNally, FM Martin, JP Crown, K Jirstrom, DG Higgins, W Gallagher
Journal: Cancer Research (2012)

Abstract Purpose: MicroRNAs (miRNAs) involved in cancer progression have now become the focus of much attention as they represent a new class of biomarkers and potential drug targets. Here, we describe an integrated bioinformatics, functional analysis and translational pathology approach for the identification of novel miRNAs involved in breast cancer progression. Experimental Design Differential gene expression can, in part, be attributed to the activity of specific miRNAs. Given a database of miRNA binding site motifs and gene expression levels determined by transcriptomic profiling, correspondence analysis, between group analysis and co-inertia analysis can be combined to produce a ranked list of miRNAs associated with a specific gene signature and phenotype. Here, using two independent breast cancer cohorts, this approach was employed to produce a ranked list of miRNAs associated with disease progression. Functional studies were subsequently carried out in MCF7 cells assessing for alterations in growth, tumorigenicity and agressiveness and miRNA expression was evaluated in two cohorts of breast cancer patients by locked nucleic acid in situ hybridisation on tissue microarrays. Results: CIA identified miR-187 as a key miRNA associated with poor outcome in breast cancer. Ectopic expression of miR-187 in MCF7 cells resulted in a more aggressive phenotype (evidenced by increased anchorage-independent growth, migratory and invasive potential). In a test cohort (n = 117) breast cancer patients, high expression of miR-187 was associated with a trend towards reduced breast cancer-specific survival (BCSS) (p = 0.058), and a significant association with reduced BCSS in lymph node-positive patients (p = 0.036). In a validation cohort (n = 470), high miR-187 was significantly associated with reduced BCSS in the entire cohort (p = 0.021) and, again, in lymph node-positive patients (p = 0.012). Multivariate cox regression analysis revealed that miR-187 is an independent prognostic factor in both TMA cohorts (Cohort 1 HR-7.369 (95% CI 2.048–26.509, p = 0.002); Cohort 2 HR-2.798 (95% CI 1.518–5.157, p = 0.001). Conclusions: miR-187 expression in breast cancer leads to the formation of a more aggressive, invasive phenotype and acts as an independent predictor of outcome. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-09-06.
Association between Early-Onset Parkinson's Disease and Mutations in the<i>Parkin</i>Gene
Authors: Christoph B. Lücking, Alexandra Dürr, Vincenzo Bonifati, Jenny Vaughan, Giuseppe De Michele, Thomas Gasser, Biswadjiet S. Harhangi, Giuseppe Meco, Patrice Denèfle, Nicholas W. Wood, Yves Agid, D. Nicholl, M.M.B. Breteler, B.A. Oostra, M. De Mari, R. Marconi, A. Filla, A.-M. Bonnet, E. Broussolle, P. Pollak, O. Rascol, M. Rosier, Arnould Arnould, Alexis Brice
Journal: New England Journal of Medicine (2000)

Mutations in the parkin gene have recently been identified in patients with early-onset Parkinson's disease, but the frequency of the mutations and the associated phenotype have not been assessed in a large series of patients.
A8.10 Cell death sensitisation in TNF-exposed IKK2-deficient synovial fibroblasts regulates disease outcome in modelled arthritis
Authors: M Armaka, G Kollias
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background and objectives</h3> Early investigations into the <i>in-vivo</i> functions of TNF in the huTNF-Tg mice established the pivotal role of this cytokine in the aetiopathogenesis of rheumatoid arthritis. We have previously demonstrated that restricted expression of p55TNFR in synovial fibroblasts (SFs) from huTNF-Tg mice is sufficient to drive the full pathogenic process. Here, we investigated whether expression of p55TNFR on SFs is necessary for the development of arthritis in either the huTNF-Tg or in Collagen-Antibody-Induced-Arthritis (CAIA) models, and how downstream SF- specific signals, such as NFkB, contribute to pathogenesis. <h3>Methods</h3> ColVI-Cre mice, providing SF-specific recombination, were crossbred into p55TNFR (p55TNFR<sup>SF-KO</sup>) or ikk2 conditional knock-out backgrounds (ikk2<sup>SF-KO</sup>) and/or into hTNF-Tg background. CAIAwas induced by injection of monoclonal antibodies against cartilage antigens, and LPS. The TNF-mediated responses of ikk2-null SFs were examined by RT-PCR, western blot and FACS analysis. <h3>Results</h3> SF-specific p55TNFR function is necessary for the development of arthritis in the huTNF-Tg model as well as in CAIA. The huTNF-Tg ikk2<sup>SF-KO </sup>and ikk2<sup>SF-KO </sup>mice subjected to CAIA exhibit ameliorated joint pathology indicating that SF ikk2 signals are required for the efficient formation of pannus. Mechanistically, ikk2-ko SFs were extremely susceptible to TNF-induced death while the huTNF-Tg ikk2-ko SFs displayed necroptotic death, suggesting a novel property of chronically TNF-exposed ikk2-deficient SFs in shifting towards necroptosis. Inhibition of necroptosis by the genetic ablation of RIPK3 kinase fully restored the residual synovial inflammation persisting in the huTNF-Tg ikk2<sup>SF-KO </sup>mice, validating <i><i>in vivo</i></i> the physiological role played by necroptosis in chronically TNF-exposed SFs in the absence of NFkB signals. <h3>Conclusions</h3> Our results demonstrate a physiologically significant role of the p55TNFR/NFkB pathway in modelled arthritis by identifying the p55TNFR/ikk2/ripk3 axis as regulator of arthritogenic responses downstream of TNF, controlling gene expression and preventing programmed cell death.
PTU-065 Influenza Vaccination uptake in Inflammatory Bowel Disease- is there Room to Improve?
Authors: D Cheema, R Muhammed
Journal: Gut (2013)

<h3>Introduction</h3> The aim of our study is to assess the seasonal influenza vaccination uptake in patients with inflammatory bowel disease (IBD) <h3>Methods</h3> We have conducted a telephonic survey of our IBD patients in February 2012 to assess the influenza vaccination uptake for winter 2011–2012. <h3>Results</h3> 140 children had responded to this survey (61.6% of our IBD patients). 84 children had Crohn’s disease, 35 had Ulcerative colitis and 21 had IBD unclassified. Majority of these children (90/140) were on immunosuppressive treatments. 61 children (44%) had received seasonal influenza vaccination in that winter. 21 of them received in October, 20 in November, 13 in December and 3 in January. Out of the 79 children who have not received the influenza vaccine, 42 were not aware of the need for vaccination and did not have the influenza vaccine in the previous winters as well. 10 children were aware of the need for the influenza vaccine; however they opted not to receive the vaccine. 14 children intended to receive the vaccine, however this was deferred due to various reasons like intercurrent illness, family bereavement and difficulties experienced the General Practice surgery. Only one IBD patient needed hospitalisation in 2011 and 2012 with Influenza infection, however this was in July before the vaccination had started. <h3>Conclusion</h3> Department of Health advises influenza vaccination for immunosuppressed individuals and also for children with medical conditions, who may need treatment with steroids for more than a month. European Crohn’s and Colitis Organisation (ECCO) recommend influenza vaccination for IBD patients on immunomodulators. Experience from Philadelphia, Boston and Poland show that good, but variable, antibody response occurs after influenza vaccination in children and better protection occurs against type A strains. Side effects, both local and systemic, are generally mild. Experience from Australia and Germany show that the seasonal flu vaccination uptake in IBD patients are generally low, 10% and 16% respectively. We would like to hear from other centres about their experience of influenza vaccination uptake in IBD patients. Further efforts need to be done to increase the awareness of influenza vaccination in patients with IBD. Influenza vaccination uptake in our IBD patients are better than reported from other centres, however further work needs to be done both locally and nationally to improve the influenza vaccination uptake. <h3>Disclosure of Interest</h3> None Declared
Hepatitis B vaccination coverage and risk factors associated with incomplete vaccination of children born to hepatitis B surface antigen-positive mothers, Denmark, 2006 to 2010
Authors: Asja Kunoee, Jens Nielsen, Susan Cowan
Journal: Eurosurveillance (2016)

In Denmark, universal screening of pregnant women for hepatitis B has been in place since November 2005, with the first two years as a trial period with enhanced surveillance. It is unknown what the change to universal screening without enhanced surveillance has meant for vaccination coverage among children born to hepatitis B surface antigen (HBsAg)-positive mothers and what risk factors exist for incomplete vaccination. This retrospective cohort study included 699 children of mothers positive for HBsAg. Information on vaccination and risk factors was collected from central registers. In total, 93% (651/699) of the children were vaccinated within 48 hours of birth, with considerable variation between birthplaces. Only 64% (306/475) of the children had received all four vaccinations through their general practitioner (GP) at the age of two years, and 10% (47/475) of the children had received no hepatitis B vaccinations at all. Enhanced surveillance was correlated positively with coverage of birth vaccination but not with coverage at the GP. No or few prenatal examinations were a risk factor for incomplete vaccination at the GP. Maternity wards and GPs are encouraged to revise their vaccination procedures and routines for pregnant women, mothers with chronic HBV infection and their children.
Abstract 1612: Targeting intercellular adhesion molecule-1 (ICAM-1) prolongs glioblastoma survival in combination with bevacizumab .
Authors: Yuji Piao, Ji Liang, Verlene Henry, Lindsay Holmes, John F. de Groot
Journal: Cancer Research (2013)

Abstract Glioblastoma is the most common malignant brain tumor and is characterized by cellular heterogeneity, vascular proliferation and extensive tissue infiltration. Analysis of gene expression data from orthotopic glioma stem cells with acquired resistance to bevacizumab therapy identified over expression of intercellular adhesion molecule 1 (ICAM1, CD54) in resistant tumors. ICAM1 is a cell adhesion glycoprotein of the immunoglobulin supergene family which interacts with β2 integrins, mediates leukocyte transendothelial migration and T cell activation during inflammatory processes. ICAM1 over expression in tumors resistant to antiangiogenic therapy was validated by real time PCR and Western blot. In a panel of glioma stem cell lines, ICAM1 expression was higher in mesenchymal compared to proneural cell lines. GFP-tagged ICAM1 shRNA lentivirus was used to knockdown ICAM1 in multiple cell lines. We injected shICAM1 NSC11 and scramble glioma stem cells into the brain of nude mice. Mice bearing tumors formed from shICAM1 NSC11 cells survived significantly longer than mice injected with scramble control cells. Tumor size was significantly decreased in mice bearing tumors formed from shICAM1 cells than that in mice bearing tumors from GFP-tagged NSC11 control cells. Knocking-down ICAM1 suppresses tumor invasion both in vitro and in vivo. We next examined the mechanism of ICAM1 over expression after treated with anti-VEGF therapy. We observed that ICAM1 over expression correlated with hypoxia-inducible factor by immnofluorescence analysis in tumor tissue. Furthermore, we found that ICAM1 protein expression was markedly increased after NSC11 and NSC17 cells under hypoxic condition in a time-dependent manner. Furthermore, hypoxia-induced p-STAT3 increased transcription of ICAM1, which was inhibited by an inhibitor of the JAK/STAT3 pathway. Our studies identify ICAM1 as a potentially important mediator of tumor migration/invasion in glioblastoma. Targeting ICAM1 may provide a new strategy to prolong the efficacy of antiangiogenic therapy and prevent the invasive phenotype. Citation Format: Yuji Piao, Ji Liang, Verlene Henry, Lindsay Holmes, John F. de Groot. Targeting intercellular adhesion molecule-1 (ICAM-1) prolongs glioblastoma survival in combination with bevacizumab . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1612. doi:10.1158/1538-7445.AM2013-1612
Abstract 2705: Quantitative targeted proteomics in pancreatic cancer: Combinations of enzyme and transporter protein expression are novel indicators for gemcitabine sensitivity
Authors: Kei Kawaguchi, Fuyuhiko Motoi, Ken Ohmine, Hideo Ohtsuka, Sumio Ohtuki, Toshiki Rikiyama, Yu Katayose, Shinichi Egawa, Tetsuya Terasaki, Michiaki Unno
Journal: Cancer Research (2010)

Abstract Background and Aims: Gemcitabine (GEM) is widely used as a first line agent for the treatment of pancreatic cancer. In some patients, it provides a long-term survival, while there are many non-responders. Recent advances in proteomics technology made it possible to quantitate trace proteins such as transporters and metabolic enzymes at high sensitivity enough to reflect the function of proteins in living organisms. In this study, we exhaustively quantitated the protein profiles of GEM related transporters and metabolic enzymes in pancreatic cancer cell lines and resected specimen using LC-MS/MS technique. We created the GEM sensitivity equation based on the profiles and the IC50 values of cell lines. This equation was validated using surgical specimens of pancreatic cancer. Materials and Methods: We used 6 pancreatic cancer cell lines for profiling. Surgical specimens from 9 patients from March 2004 to January 2006 were classified GEM respond group (RS), GEM non-respond group (NR) and surgery effect group (SE) according to post-operative CA 19-9 value. The expression levels of 90 membrane proteins and 15 enzymes were quantified in 6 pancreatic cancer cell lines and 9 surgical specimens, by means of multiplexed MRM analysis with LC-MS/MS. Results: Significant differences in the expression levels of dCK and Purine-5-NT were observed between responsive and non-responsive groups of patients, although no correlation of the expression levels of these proteins with IC50 of gemicitabine was found in the cell lines. The expression levels of ten membrane proteins in the cell lines were correlated to IC50 of gemcitabine, but the expression levels of these proteins failed to predict the gemcitabine sensitivity of cancer tissues. Next, expression ratios of multiple proteins (transporters and enzymes) that were present in cancer tissues were calculated for the cell lines. dCK/(MRP1+MRP4), dCK/(MRP1+MRP4+Purine-5NT), dCK/(MRP1+MRP4+CTPS1) and dCK/(MRP1+MRP4+Purine-5NT+CTPS1) showed high correlation with IC50 values. For all four combinations, the protein expression ratio in the RS group was significantly higher than those in NR and SE groups. Conclusion: Applying these equations, we can predict GEM sensitivity and tailor-made chemotherapy can be implemented. 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 2705.