tbuckley/cabot-search huggingface dataset:
Abstract 1158: Single step multiplex amplification and barcoding of FFPE samples for Next-Gen sequencing
Authors: Magnus Isaksson, Henrik Johansson, Fredrik Roos, Elin Falk, Lotte Moens, Olle Ericsson, Mats Nilsson
Journal: Cancer Research (2010)

Abstract We present data outlining application of the Selector Technology to successfully amplify and sequence sets of exons in both fresh frozen and formalin fixed paraffin embedded tumor samples. We also show preliminary data where the Selector Technology has been adapted to incorporate sequencing primers and barcodes during amplification thereby replacing the laborious sample preparation with a single PCR step which open up for streamlined large scale parallel sample preparation of patient cohorts. The technology has been scaled to amplify as many as 17,000 amplicons in one single reaction tube. The Selector Technology is suitable for convenient and scalable single tube amplification of large sets of genes. The technology provides unbiased amplification of exons for resequencing providing unparalleled on target alignment of &amp;gt;95% of reads mapping to amplified regions and &amp;gt;90% of exon base bp at 20-30% of average amplicon sequencing depth providing cost effective high coverage resequencing. Concordance with HapMap genotypes is 99% and the reproducibility (R2) between replicates is 0.98 at the single nucleotide level. High reproducibility provides the possibility to score copy number variations in tumor samples as well as calling copy number neutral loss of heterozygosity. These features are demonstrated using matched tumor-normal breast cancer samples. Conclusively, the Selector Technology is a convenient, high performance technology for large scale sample preparation of cancer samples. 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 1158.
PTH-020 Retrospective Cohort Study To Determine The Optimum Frequency Of Surveillance Colonoscopy For Patients With Intermediate Grade Colorectal Adenomas In The Uk
Authors: A Brenner, P Greliak, J Martin, K Pack, U Shah, W Atkin
Journal: Gut (2014)

<h3>Introduction</h3> Colonoscopic surveillance for colorectal cancer (CRC) is widely practiced; however, there remains a lack of evidence to determine appropriate surveillance intervals for individuals at intermediate risk (IR) of CRC. Due to the considerable strain on endoscopic resources and serious cost implications, it is vital to optimise surveillance strategies to ensure colonoscopy is targeted at those who will benefit most. This study examines the frequency of surveillance in patients with intermediate grade (IG) adenomas, aiming to assess whether there is significant heterogeneity in the detection of advanced neoplasia within this group, according to baseline findings and surveillance interval length. <h3>Methods</h3> A retrospective cohort design was used in a secondary care setting. 18 UK hospitals were selected based on the availability of electronic patient data suitable for automatic extraction. Endoscopy reports containing Systematised Nomenclature of Medicine codes or words relating to adenomas were identified and linked to corresponding pathology records. These were extracted from hospital databases before being pseudo-anonymised, formatted and uploaded onto an APEX database to be interpreted and coded. Patients were excluded from the analysis if they had no IG adenomas, no baseline colonoscopy, any missing exam dates or conditions affecting CRC risk. Baseline and follow-up visits, and polyp characteristics, were defined using a series of rules developed by the study team. Outcome measures used were advanced adenomas (AA) and CRC; information on these was obtained using follow-up data from external sources, in addition to the hospital data. Analysis of risk of AA and CRC at each follow-up visit, according to baseline findings and interval length, will be performed through the use of descriptive statistics and logistic regression. Approval was obtained from the National Research Ethics Service, Caldicott Guardians and the National Information Governance Board. As it was not feasible to seek patient consent, patient confidentiality was ensured through pseudo-anonymisation of data. <h3>Results</h3> Endoscopy and pathology data from over 200,000 patients was collected and coded, and a large bespoke database was created to store this data. A total of 11,995 IR patients with a baseline colonoscopy were identified for analysis, 4,694 of whom have at least one follow-up visit. <h3>Conclusion</h3> Analysis of the data is currently in progress. When completed, later this year, conclusions will be drawn on the optimal surveillance intervals for IR patients. The database will also act as a unique resource for further studies involving patients at both low and high risk, and for examining the association between serrated lesions and proximal CRC. <h3>Disclosure of Interest</h3> None Declared.
Preferential chemosensitivity to gemcitabine by cyclin E overexpression in human gastric cancers
Authors: K. Yeh, Y. Shen, Y. Chiang, P. Liu, C. Huang, A. Cheng
Journal: Journal of Clinical Oncology (2007)

21020 Background: Exploration of molecular determinants for chemosensitivity is the key element of personalized cancer therapy. Cyclin E is a major G1-phase cyclin, together with the CDK2, which mediates phosphorylation and functional inactivation of Rb protein. Cyclin E overexpression has been demonstrated in a variety of cancers, including human gastric cancers (GC), while its biologic significance in drug therapy remains unclear. Previously, we have demonstrated that cyclin D1 overexpression plays an important role in differential chemosensitivity of human GC cells (Proc Am Assoc Cancer Res 2004; 45: abstract 4888). In this study, we examine the roles between cyclin E overexpression and chemosensitivity of human GC cells. Methods: Compared human gastric cancer cells (NCI-N87) with stably transfected cells (N87-CyE), which have 2-fold overexpression of cyclin E, the IC 50 for gemcitabine (2'-2'-difluoro- deoxycytidine, dFdC) was more than 1-log lower in N87-CyE (17.0 ± 2.7 nM) than N87 cells (113.7 ± 6.5 nM) by MTT colorimetric cytotoxicity assay. In contrast, the N87-CyE cells are only slightly more chemosensitive to taxanes (paclitaxel and docetaxel), and confer largely identical chemosensitivity to 5-FU, cisplatin, and irinotecan (CPT-11). We applied RNA interference (RNAi) of cyclin E to N87 cells. The stably transfected N87-CyE/RNAi cells readily confer gemcitabine resistance with the IC 50 for gemcitabine of 124.5 ± 1.6 nM. Results: Gemcitabine-induced apoptosis in N87, N87-CyE, or N87-CyE/RNAi cells was shown in either caspase-3 or PARP (poly ADP-ribose polymerase) cleavage assay by Western blotting, and Annexin-V-FITC apoptosis detection by flowcytometry. The threshold concentration of gemcitabine for caspase-3 and PARP cleavage was 10–25 nM for N87-CyE, and 100–200 nM for N87 or N87-CyE/RNAi, respectively. Conclusions: Our data demonstrate that preferential chemosensitivity to gemcitabine by cyclin E overexpression in gastric cancer cells. Gemcitabine-induced apoptosis is enhanced by cyclin E overexpression, while is reduced by RNAi of cyclin E. Further studies for potential clinical use of gemcitabine in personalized chemotherapy for cyclin E or cyclin D1-overexpressing GC are warranted (supported by the grants of NHRI-CN-CA9201S, Taiwan). No significant financial relationships to disclose.
SP0077 Inflammasomes - powerhouses of intracellular innate immune responses
Authors: F. Martinon
Journal: Annals of the Rheumatic Diseases (2013)

The innate immune system has evolved the capacity to detect specific pathogens and to interrogate cell and tissue integrity in order to mount appropriate immune responses. Pathogens are detected by innate immune receptors including NLRs and TLRs. Some NLRs, including NALPs (NLRPs), form molecular machines termed inflammasomes. The recruitment of the adaptor ASC and the enzyme caspase-1 to the inflammasome platform are crucial for its activity that mainly control the proteolytic maturation of a few key inflammatory cytokines such as IL-1beta and IL-18. The mechanisms that regulate the activation of inflammasomes are poorly understood. Here we will discuss how perturbations of cellular homeostasis including endoplasmic reticulum (ER) stress trigger the assembly of the NLRP3 inflammasome. These findings suggest new mechanistic insights linking stress pathways and inflammatory diseases. <h3>Disclosure of Interest</h3> None Declared
Perforation of the splenic artery as a complication of endoscopic pancreatic stent placement in chronic obstructing pancreatitis
Authors: J. Pelz, M. Farnbacher, M. Raithel, A. Hagel, O. Herrmann, W. Hohenberger, S. Straube, P. Klein
Journal: Endoscopy (2013)

Endoscopic pancreatic duct stenting is a widely used treatment option for pancreatic duct stenosis in chronic pancreatitis. In approximately 5 % – 10 % of cases, the procedure itself causes adverse events. Major limitations of pancreatic endoprosthesis therapy are stent dislocation, stent occlusion, and post endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis [1]. Because its long-term benefit is also limited compared with duodenum-preserving pancreatic head resection [2] [3], stenting of pancreatic duct stenosis is still debated and is recommended only as a temporary measure to date [4].
A5.6 Cholecystokinin and purinoreceptor antagonists modulate OA-associated GPR22 signalling
Authors: Laura-An Guns, Frédéric Cailotto, Rik J. Lories
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Osteoarthritis (OA) is the most common type of arthritis and its prevalence increases in the ageing population. A genome-wide association study (GWAS) identified an OA susceptibility locus of approximately 500 kb on chromosome 7q22. This locus contains a linkage disequilibrium block of six genes that includes G protein coupled receptor protein 22 (GPR22). GPR22 signalling inhibits protein kinase A (PKA) activity but its ligand is unknown. GPR22 shares 37% sequence homology with the Cholecystokinin B receptor (CCK-BR) and is predicted to belong to the purinergic P2Y12 family. Here we aim to further study the role of GPR22 in cartilage. <h3>Methods</h3> We used the ATDC5 chondrogenic cell line as model system. Stably overexpressing GPR22 cells (GPR22+) were cultured in triplicate as high density micromasses (200 000 cells/10 µl). Cells were treated daily with ITS in DMEM/F12 medium for 14 days to induce chondrogenesis. Mineralization was triggered with beta-glycerol-phosphate in α-MEM medium till day 21. Different chemical compounds were added: CCK-BR antagonist AG-041R (1 and 10 µM), broad-spectrum purinoreceptor antagonist suramin (10, 33 and 100 µM) and PKA activator 8-Br-cAMP (10 and 33 µM). Gene expression of CCK-BR and chondrogenic markers, including Aggrecan (Agg), Decorin (Dco), Versican (Vcan), Collagen type 2 (Col2a1) and type 10 (Col10a1) and Matrix metalloprotease 13 (MMP13), were analysed. Sulfated proteoglycan, mineralization and collagen content were quantified by Alcian Blue, Alizarin Red, Safranin O and Picosirius Red staining. <h3>Result</h3> Overexpression of GPR22 stimulates chondrocyte hypertrophy and accelerates calcification. CCK-BR expression was not detected in ATDC5 cells. AG-041R 1 µM increased Agg, Col2a1, Col10a1 expression at day 1 compared to unchallenged cells. Additionally, on day 21 the amount of proteoglycan and calcium deposition was increased. The use of 10 µM AG-041R and of 100 µM suramin was toxic for cells. However, 10 µM suramin treatment lead to increased decorin and versican expression. This translated into increased proteoglycan (and collagen) levels in the extracellular matrix (ECM). 8-Br-cAMP increased mRNA expression of Agg, Col2a1 and Col10a1. <h3>Conclusion</h3> A cholecystokinin antagonist and the broad spectrum purinoreceptor antagonist slightly compensate for the effect of GPR22 overexpression on chondrogenesis. The PKA activator, 8-Br-cAMP did not change the GPR22 phenotype at the ECM level, but induced subtle transcriptomic changes.
P26 P38 MAPK Inhibition Enhances Corticosteroid Effects In Human Epithelial Cells Via Increased Gr Nuclear Localisation
Authors: S. Lea, K. Gaffey, J. Plumb, R. Gaskell, D. Singh
Journal: Thorax (2014)

<h3>Background</h3> Phospho-p38 MAPK expression is increased in airway epithelial cells in patients with severe asthma and in COPD patients compared to controls. Increased p38 MAPK activation may lead to reduced corticosteroid responsiveness. We have used a human cell bronchial epithelial cell line to investigate the effects of a p38 MAPK inhibitor in combination with a corticosteroid on inflammatory cytokine stimulation. <h3>Methods</h3> The human epithelial cell line 16HBE14o<sup>-</sup> was used to determine the effects of dexamethasone (0.1–1000 nM) alone, the p38 MAPK inhibitor BIRB-796 (1–1000 nM) alone and both drugs combined at all concentrations on LPS (1 µg/ml), Poly I:C (100 µg/ml) or TNFα (10 ng/ml) -induced IL-6, IL-8 and RANTES. 16HBE14o<sup>-</sup> cells were treated with BIRB-796 (1–1000 nM) alone and in combination with dexamethasone (0.1 nM) for 30 min and glucocorticoid receptor (GR) nuclear translocation determined by immunofluorescence. The effects of TNFα stimulation on the phosphorylation of p38 and GR (serine 226) in 16HBE14o<sup>-</sup> cells were determined by Western blot analysis. <h3>Results</h3> Maximum inhibition of dexamethasone and BIRB-796 in combination was significantly greater than either drug alone for LPS and TNFα induced IL-6 and IL-8 and for Poly I:C induced RANTES (p &lt; 0.05 all comparisons). BIRB-796 (1000 nM) alone had no effect on GR translocation. BIRB-796 (1000 nM) used in combination with dexamethasone (0.1 nM) significantly increased nuclear GR (76.6% nuclear staining) compared to dexamethasone (0.1 nM) alone (4% nuclear staining). TNFα stimulation increased both p38 and GR serine 226 phosphorylation by 15 min. Pre-incubation with BIRB-796 abolished p38 phosphorylation and reduced GR serine 226 phosphorylation. <h3>Conclusion</h3> P38 MAPK inhibition enhances the effect of corticosteroids on inflammatory cytokines in human epithelial cells. This enhancement is due to inhibition of p38 dependent phosphorylation of GR serine 226 which leads to increased nuclear localisation of GR.
Abstract 5024: Epigenetic regulation of cancer stem cell states in a p53/PTEN inactivated mammary epithelial cells.
Authors: Maria Ouzounova, April Davis, Gwangil Kim, Fayaz Malik, Ahmed A. Quraishi, Shawn G. Clouthier, Max S. Wicha, Hasan Korkaya
Journal: Cancer Research (2013)

Abstract Inactivation of the tumor suppressors, TP53 and PTEN in pre-neoplastic lesions has been implicated in tumor progression as well as in regulation of normal and malignant stem cell self-renewal. Down regulation of both p53 and PTEN in non-transformed MCF10A cells synergized to expand the cancer stem cell compartment transforming these cells and generating an EMT phenotype in vitro which generated highly metastatic tumors when injected in NOD/SCID mice. These tumors could be fractionated based on their expression of CD49f and EPCAM. Gene expression analyses of these sub-fractions demonstrate an EMT gene signature in CD49f+/EPCAM- and CD49f-/EPCAM- cell populations. These findings are also supported by DNA methylation analyses. Although CD49f+EPCAM+ cell population express epithelial (MET) gene signature, these cells also generate tumors in mice and give rise to cells with EMT phenotype. Interestingly CD49f+EPCAM+ subpopulation expresses higher ALDH than other two subpopulations with EMT phenotype. Therefore we propose that breast CSCs may exist in two states; EMT state may be represented by CD49f or CD44 and MET state by ALDH expression. Consistent with our hypothesis, ALDH-positive cells compared to ALDH-negative cells within the CD49f+EPCAM+ phenotype have greater capacity to generate CD49f+/EPCAM- phenotype upon IL6 or TGF-b stimulation. Interestingly blocking IL6 and TGF-b in CD49f+/EPCAM- cell population results in MET-CSC phenotype characterized by ALDH expression. It is well known that EMT is characterized by reversible epigenetic changes and therefore we hypothesized that these epigenetic changes might be involved in acquisition of different CSC states. Our results suggest that interplay between genetic and epigenetic changes during malignant transformation of mammary epithelial cells may activate multiple signaling cascades resulting in expansion of stem cells which display an EMT phenotype. Furthermore, these studies provide a strong rationale for the development of alternative therapeutics which are able to target these different states of cancer stem cells. Citation Format: Maria Ouzounova, April Davis, Gwangil Kim, Fayaz Malik, Ahmed A. Quraishi, Shawn G. Clouthier, Max S. Wicha, Hasan Korkaya. Epigenetic regulation of cancer stem cell states in a p53/PTEN inactivated mammary epithelial cells. [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 5024. doi:10.1158/1538-7445.AM2013-5024
Pancreatic Metastasis Detected by F-18 FDG PET/CT in a Patient With Breast Cancer
Authors: Winnie Wing-Chuen Lam, Kelvin Siu-Hoong Loke, Hoi Yin Loi, Ajit Kumar Padhy
Journal: Clinical Nuclear Medicine (2011)

Pancreatic involvement by metastasis from other primaries is rare and accounts for approximately 2% to 4% of pancreatic tumors. In this article, we describe FDG-avid pancreatic involvement in a patient with diagnosis of breast cancer. We conclude that FDG PET can be a convenient noninvasive method of early detection of recurrence and in monitoring metastatic disease during follow-up in such patients. A positive FDG PET warrants histopathologic correlation for appropriate treatment.
Abstract 2502: Swallowed small molecule GS-nitroxide, JP-4-039, protects the irradiated esophagus
Authors: Michael W. Epperly, Joel S. Greenberger, Hyun Kim, Mark Bernard, Tracy Dixon, Darcy Franicola, Peter Wipf, Song Li, Xiang Gao, Valerian Kagan, Andrew Amoscato, Hongmei Shen
Journal: Cancer Research (2011)

Abstract Irradiation induced esophagitis is a dose limiting factor in the treatment of lung cancer, and limits irradiation dose escalation. Intraesophageal manganese superoxide dismutase plasmid liposomes has been shown to protect against irradiation esophagitis (Tarhini, et.al. Human Gene Therapy, in press). A new small molecule drug recently has shown irradiation protection and mitigation in vitro. The new drug (JP4-039) is a nitroxide attached to a mitochondrial targeting sequence. Drug was delivered to the top of the esophagus and the mouse swallowed the F15 formulation, consisting of soy PC: Tween-80: L-glutamyl dioleylamide (4:1:1 w/w) and 8 mg/ml of JP4-039 in PBS. C57BL/6NHsd mice swallowed 100 µl water followed by 100 µl F15-JP4-039 (0.4 mg/mouse) ten minutes before 28 Gy to the upper body. F15-JP4-039 resulted in a significant increase in survival compared to irradiated controls. F15-JP4-039 produced a 30 day survival of 75% compared to 30% for irradiation control (p = 0.0315). The JP4-039 nitroxide signal, detected by EPR, allowed demonstration that drug was in whole esophagus and in the esophageal stem cells. F15-JP4-039 intraorally treated mice were sacrificed at 10 min, 30 min, 1 hr or 5 hr after swallowing the F15-JP4-039, esophagus removed, single cell suspensions made, frozen, and analyzed by EPR. At 10 min, 2971.3 fmoles of JP4-039/million cells were detected, and still detected out to 5 hours, 1081 fmoles/million cells, after irradiation. Sorted side population cells (SP), enriched for stem cells, and nonside population cells (NSP) isolated by flow cytometer were analyzed at 10 min after swallow, by EPR for JP4-039 uptake. The SP cells had 3666.7 fmoles per million cells and the NSP cells had 73.7 fmoles nitroxide per million cells demonstrating that drug had reached stem cells. Thus, intraesophageal administration of small molecule antioxidant GS-nitroxide reduces murine radiation esophagitis, and may be a valuable translational radiation protector to ameliorate clinical esophagitis in lung cancer patients. Supported by 2U19A1068021-06 and RO1-CA83876-06 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 2502. doi:10.1158/1538-7445.AM2011-2502
Vermont governor agrees to sign bill on physician assisted suicide
Authors: M. McCarthy
Journal: BMJ (2013)

Vermont is on the verge of becoming the third US state to allow physicians to prescribe lethal doses of drugs to terminally ill patients who request the prescriptions.

Oregon and Washington states have also adopted similar legislation through voter referendums, but Vermont is the first eastern state to pass a law and the first in the nation to pass it through a vote of a state legislature.

Vermont passed the legislation on 13 May, and governor Peter Shumlin has said that he will sign the legislation into law.

“I understand …
DO THE NEW POOLED COHORT EQUATIONS AGREE WITH REYNOLD’S RISK SCORE FOR WOMEN?
Authors: Eric R. Silverman, Briana T. Costello, Nicole Pohlman, Benjamin Gastevich, Josephine Kooijman, Rasa Kazlauskaite, Gina Lundberg, Noreen Nazir, Youping Deng, Yan Li, Bala Hota, Lynne T. Braun, Kim A. Williams, Annabelle S. Volgman
Journal: Journal of the American College of Cardiology (2015)
P225 Revised Bts Guidelines For Securing Cancer Diagnosis At Bronchoscopy - A Higher Recommended Yield Is Realistic And Achievable
Authors: A. Stanton, C. Mackinlay
Journal: Thorax (2014)

<h3>Introduction</h3> The recently updated BTS guidelines<sup>1</sup> on bronchoscopy recommend that a diagnostic level of 85% should be attainable when definite endobronchial tumour is visible, an increase from previous recommendation of 80%. We investigated whether this higher level was achievable. <h3>Methods</h3> All patients undergoing bronchoscopy for suspected lung cancer were prospectively entered into a departmental database from April 2010, with performance analysed annually. The following specific data were entered: level of tumour presence (none seen / possible / definite tumour); diagnostic specimens taken (biopsy, brush, wash, TBNA); result of each diagnostic specimen (tumour present / not present, with reports “suspicious or suggestive” of tumour classified as “not present” unless there was a specific MDT decision to give a cancer diagnosis), and whether bronchoscopy was diagnostic of lung cancer overall. Finally clinical records were reviewed in patients without a bronchoscopic diagnosis of cancer to determine their final diagnosis. <h3>Results</h3> In the 4 full years since commencement of data collection, 356 bronchoscopies were performed for suspected lung cancer, with confirmed cancer diagnosis in 301. Table 1 summarises diagnostic sensitivity for endobronchial biopsy, brush, wash and overall sensitivity for lung cancer diagnosis at bronchoscopy in patients with bronchoscopically definite tumour seen. In 3/4 years our overall diagnostic sensitivity has reached the level recommended (86.4–91.7%), with first year performance just below the new standard (84.4%). <h3>Conclusions</h3> The revised level of recommended diagnostic rate at bronchoscopy for definite tumour appears to be realistic and achievable. This should remain as the standard of care for patients undergoing bronchoscopy for suspected lung cancer. <h3>Reference</h3> BTS Guideline for diagnostic flexible bronchoscopy in adults. Thorax 2013;68(Suppl 1)