tbuckley/cabot-search huggingface dataset:
DD-01 * LIGAND- AND STRUCTURE-BASED VIRTUAL SCREENING TO DISCOVER POLYPHARMACOLOGICAL DUAL EGFR AND BRD4 INHIBITORS
Authors: B. Allen, S. Mehta, N. Ayad, S. Schurer
Journal: Neuro-Oncology (2014)

Combination therapy is the standard-of-care for many cancer patients. The standard treatment for Glioblastoma Multiforme (GBM) includes surgical resection, followed by radiotherapy, and temozolomide (TMZ) subministration. However, resistance to TMZ is nearly universal and tumor recurrence is inevitable. Thus, it is desirable to identify effective combination therapies for the treatment of GBM and other aggressive cancers. Recently, bromodomain-containing protein 4 (BRD4) is emerging as an interesting target for drug development for a large number of diseases that are caused by aberrant acetylation of lysine residues, among these cancer. We propose to overcome this problem by generating kinase inhibitors, which also inhibit epigenetic enzymes. We describe a virtual screening approach to identify compounds that are likely to inhibit both BRD4 and epidermal growth factor receptor beta (EGFR) using in silico analysis, docking, and laplacian based modifier algorithms to predict relative ligand-receptor dynamics. Key elements of this approach include algorithmic prediction of EGFR inhibition based on chemical similarity and quantitative structure activity relationships, protein-ligand docking from crystal structure analysis and preparation, and substructure queries to compile a set of commercially available compounds that can be ordered for in vitro assays. We will confirm inhibitory activity of BRD4 by selected compounds via an AlphaLisa Bromodomain-Aceylated Histone H4 Interaction Assay. Of 108 hits from the docking study, 24 compounds were selected for validation. Our preliminary results show promising activity of one compound from our AlphaScreen Assay. We will be testing the efficacy of these drugs in patient derived cancer cells in the near future. With this approach, we can unveil new properties of compounds that can inhibit both BRD4 and EGFR. We also show the validation of our chemoinformatic pipeline, which can be used for additional drug discovery efforts and to further explore the field of polypharmacology.
PTU-012 Development Of Standards For Delivery Of Training In Gastroenterology: Defining Quality And Providing Accurate Assessment Of Units
Authors: E Britton, S Sarkar, PK Flanagan
Journal: Gut (2014)

<h3>Introduction</h3> Training in Gastroenterology is currently defined by the JRCPTB curriculum. Whilst some guidance is provided on composition of clinical sessions its main focus is on overall training structure and expected clinical competencies and knowledge levels. Delivery of training is commonly arranged locally but there are currently no defined standards to describe the expected structure and standard of training within hospital placements. Consequently quality of training can be extremely variable. For the first time we present comprehensive standards detailing the delivery of high quality training in Gastroenterology. <h3>Methods</h3> <h3>Aims</h3> To develop and validate standards for delivery of training in Gastroenterology. <h3>Methods</h3> Standards were developed by consensus opinion by trainees and consultants including those with relevant subspecialist interests. Refinement of the standards was achieved by further peer review and pilot studies. In all there were 10 domains (inpatients, outpatients, endoscopy, HPB, IBD, luminal, nutrition, GIM, education, teaching) each with 5 possible grades (unacceptable, minimum, average, good, excellent). All points within the lowest grade had to be achieved before higher grade could be awarded. All units were then assessed against the standards with completion of the form by consensus trainee opinion. Overall assessment of individual units was also performed by consensus opinion and using a likert scale. <h3>Results</h3> 9 hospitals were assessed and significant variations in training quality were identified with large variation in overall grade attainment (range 22–94%). Overall grade and% grade attainment correlated accurately with overall consensus opinion on the relative strengths of units. Poorly performing units were reliably identified and relative strengths of units highlighted. Likert scale assessment was shown to be unreliable with consistently high scores across all units even when overall assessment was poor. <h3>Conclusion</h3> Formal standards define how to deliver high quality training, allow objective assessment of units and highlight specific deficiencies in training enabling targeted improvement in delivery. The standards were more reliable than existing methods of assessment. These standards hold the potential to significantly improve training in Gastroenterology in the UK. <h3>Disclosure of Interest</h3> E. Britton: None Declared, S. Sarkar: None Declared, P. Flanagan Grant/research support from: Awarded a Shire innovation fund for SpRs.
Abstract 579: The interaction of ZSCAN4 with TRF1: effects on regulation of telomere elongation in cancer cells.
Authors: kyungwoo lee
Journal: Cancer Research (2013)

Abstract Telomeres are repetitive sequences at the ends of chromosomes protected by DNA binding proteins of shelterin complex that form capping structures. One of these proteins, TRF1, plays a role in the regulation of telomere length through its interaction with other proteins in the shelterin complex. High levels of TRF1 expression have been shown to accelerate telomere shortening, whereas dominant-negative inhibition of TRF1 leads to telomere elongation. Recently, the newly identified Zinc finger and SCAN domain containing4 gene (ZSCAN4) plays a key role in genomic stability by regulating telomere elongation and was shown to co-localize with TRF1 foci in mouse embryonic stem cell. Here, we show that ZSCAN4 is a TRF1 association protein in breast cancer cells. We hypothesized that ZSCAN4 would affect levels of TRF1expression and correspondingly control the function of TRF1 through negative regulation and dominant-negative inhibition. Using Co-immunoprecipitation and TNT Pull-down assay, we demonstrate that ZSCAN4 binds with TRF1 in vitro. Localization and visualization of interacting protein-protein interactions in living cells are crucial to elucidate between TRF1 and ZSCAN4. Using a bimolecular fluorescence complementation (BiFC) assay, we show the directly visualize TRF1 and ZSCAN4 interactions in living cells. Using telomere length assays, we demonstrate that ZSCAN4 is an association protein of TRF1 to regulate telomere and affect in the telomere elongation of cancer. The ZSCAN4 mediated cooperative binding of TRF1 to telomeric DNA has important implications for understanding the mechanism of telomere extension. Citation Format: kyungwoo lee. The interaction of ZSCAN4 with TRF1: effects on regulation of telomere elongation in cancer 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 579. doi:10.1158/1538-7445.AM2013-579
Abstract 4721: Adaptation to histone deacetylase inhibitors attenuates cancer cell growth
Authors: Hsin-Ching Lin, Catherine Liu, Amrita Aranake, Arnold B. Rabson
Journal: Cancer Research (2012)

Abstract Histone deacetylase (HDAC) inhibitors, such as SAHA (suberoylanilude hydroxamic acid) inhibit the growth of multiple cancer cell lines in vitro, and human tumor xenografts in vivo. SAHA has recently been approved for the treatment of human T cell lymphomas and is in clinical trials for a number of other different malignancies. HDAC inhibitors lead to increased acetylation of multiple cellular proteins, including histones, and lead to major changes in cellular gene expression, however the precise mechanisms of their therapeutic effects are not known. HDAC inhibitors have been reported to have multiple effects on different cancer cell lines, ranging from induction of differentiation to induction of apoptosis, DNA damage, senescence, and autophagy. We hypothesized that chronic treatment of malignant cells with HDAC inhibitors, through changes in the program of cancer cell gene expression, would induce differentiation and senescence, and attenuate the malignant phenotype. We have treated a subclone of the SW480 colon cancer cells (S3 cells) with step-wise increasing amounts of SAHA. Chronic treatment with SAHA resulted in adaptation of S3 cells to SAHA, associated with marked decrease in cell growth and tumorigenicity in nude mice. In addition to slow growth, SAHA-adapted SW480 cells (designated SH80), exhibit features of differentiation including gland formation and increased intestinal alkaline phosphatase production (IAP), and increased cell size, associated with multiple nuclei and polyploidy. Interestingly, decreased growth rate and increased expression of alkaline phosphatase were seen even following drug withdrawal, suggesting that drug-adaptation resulted in a relatively stable phenotype. Frequent expression of senescence-associated β-galactosidase was observed in SH80 cells, particularly in giant cells and cell clusters, suggesting on-going senescence. Increased expression of p21 RNA and protein, previously suggested to contribute to the growth inhibition effect of HDAC inhibitors, was observed in the SH80 cells. SH80 cells also exhibited changes in the expression of several microRNAs previously implicated in oncogenesis, suggesting that altered expression of these miRs might contribute to the attenuated malignant phenotype in SH80 cells. These data suggest adaptation of colon cancer cells to HDAC inhibitor therapy may attenuate key aspects of the malignant phenotype, and offer a new therapeutic approach to the long-term control of cancer. 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 4721. doi:1538-7445.AM2012-4721
Hyperuricaemia: contributions of urate transporter ABCG2 and the fractional renal clearance of urate
Authors: Diluk R W Kannangara, Amanda J Phipps-Green, Nicola Dalbeth, Lisa K Stamp, Kenneth M Williams, Garry G Graham, Richard O Day, Tony R Merriman
Journal: Annals of the Rheumatic Diseases (2015)

To investigate the contributions towards hyperuricaemia of known risk factors, focusing on fractional (renal) clearance of urate (FCU) and variation in the ATP-binding cassette transporter, sub-family G 2 (ABCG2) gene.The contributions of age, sex, ancestry, Q141K genotype for ABCG2, FCU, sugar-sweetened beverage and alcohol consumption, metabolic syndrome disorders and measures of renal function to the risk of hyperuricaemia were evaluated by comparing hyperuricaemic (serum urate≥0.42 mmol/L, n=448) with normouricaemic (serum urate<0.42 mmol/L, n=344) participants using stepwise logistic regression. Model performance was evaluated using the area under the receiver operator characteristic curve (AUROC).ABCG2 genotype, FCU, male sex, body mass index, serum triglyceride concentrations, estimated glomerular filtration rate and consumption of alcohol were the best predictors of hyperuricaemia (AUROC 0.90, 81% accuracy). Homozygosity in the 141K variant for ABCG2 conferred an adjusted OR of 10.5 for hyperuricaemia (95% CI 2.4 to 46.2). For each 1% decrease of FCU, the adjusted OR increased by 51% (OR 1.51, 95% CI 1.37 to 1.66). There was no association between ABCG2 genotype and FCU (r=0.02, p=0.83).The ABCG2 141K variant and the FCU contribute strongly but independently to hyperuricaemia. These findings provide further evidence for a significant contribution of ABCG2 to extra-renal (gut) clearance of urate.
Scintigraphic Appearance of Dilated Marginal Artery of Drummond
Authors: K. KUMARESAN, J. VENKATESHWARLU, B. V.R. MURTHY
Journal: Clinical Nuclear Medicine (1996)

A 27-year-old man underwent dynamic imaging with Tc-99m DTPA to evaluate an autotransplanted left kidney. Aortoarteritis with ostial occlusion of the left renal artery was the preoperative diagnosis. An abnormal dilated and tortuous vessel was visualized in the abdomen during the vascular phase of the scan performed in the anterior view, in addition to satisfactory perfusion of the auto-renal graft in left iliac fossa(Fig. 1). Review of the MRI and abdominal aortogram (Fig. 2) confirmed the vessel to be a dilated collateral marginal artery of Drummond that 1developed after occlusion of the superiormesenteric artery.
Serum Cholesterol in Young Men and Subsequent Cardiovascular Disease
Authors: Michael J. Klag, Daniel E. Ford, Lucy A. Mead, Jiang He, Paul K. Whelton, Kung-Yee Liang, David M. Levine
Journal: New England Journal of Medicine (1993)

The increased risk of cardiovascular disease associated with higher serum cholesterol levels in middle-aged persons has been clearly established, but there have been few opportunities to examine a potential link between serum cholesterol levels measured in young men and clinically evident premature cardiovascular disease later in life.
CENTRAL CARDIAC OUTPUT REDISTRIBUTION DUE TO SEVERE MITRAL REGURGITATION IN ADVANCED HEART FAILURE IS ASSOCIATED WITH A HIGHER OXYGEN PERIPHERAL EXTRACTION
Authors: Greta Generati, Bandera Francesco, Marta Pellegrino, Valentina Labate, Valeria Donghi, Vincenzo Tufaro, Eleonora Alfonzetti, Marco Guazzi
Journal: Journal of the American College of Cardiology (2016)
NIH:Recruiters Take Their Toll
Authors: C. Vanchieri
Journal: JNCI Journal of the National Cancer Institute (1989)

Journal Article NIH:Recruiters Take Their Toll Get access Cori Vanchieri Cori Vanchieri Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 81, Issue 1, January 1989, Pages 5–7, https://doi.org/10.1093/jnci/81.1.5 Published: 01 January 1989
Abstract 4806: Association of changes in 4-aminobutyrate aminotransferase (ABAT) and beta-alanine metabolism with breast cancer and the more aggressive estrogen receptor negative subtype
Authors: Jan Budczies, Annika Lehmann, Jules L. Griffin, Matej Oresic, Oliver Fiehn, Carsten Denkert
Journal: Cancer Research (2012)

Abstract Metabolic changes are the final answer of the cell to environmental or genetic changes. While gene expression in breast cancer has extensively been studied, studies on the breast cancer metabolome and its correlation to transcriptional changes are rare. Therefore, a combined metabolomics and transcriptomics study was carried out by the METAcancer consortium. In this project, 275 breast cancer tissues collected as fresh-frozen samples in the METAcancer tumor bank were analyzed using gas chromatography combined with time of flight mass spectrometry (GC-TOF-MS). Out of these, 156 tumor samples were transcriptionally profiled using whole genome DASL. Before, we identified 10 increased and 9 decreased metabolites in the more aggressive estrogen receptor negative (ER-) compared to the estrogen receptor positive (ER+) breast cancer (poster #5573, AACR Annual Meeting 2010). Among these changes, the increase of beta-alanine (fold change = 2.4, p = 1.7E-20) was the strongest and most significant alteration. Comparing breast cancer and normal tissues, beta-alanine turned out to be strongly increased in the cancer tissues (fold change = 2.6, p = 1.1E-34). Using the Kyoto Encyclopedia of Genes and Genomes (KEGG) we identified 135 enzymes that catalyze reactions of the 19 regulated metabolites. These enzymes were subjected to correlation analysis with their substrates and products. As most significant result, a negative relationship between 4-aminobutyrate aminotransferase (ABAT) expression and beta-alanine concentration was detected (Pearson correlation = –0.62, p = 1.1E-17). ABAT was significantly down-regulated in the more aggressive ER- subtype (fold change = –1.9, p = 1.6E-08). The differential expression of ABAT was confirmed in three publicly available breast cancer microarray data sets. The effect of ABAT inhibition was investigated in estrogen receptor positive MCF-7 and triple-negative MDA-MB-231 breast cancer cells. In both cell lines, treatment with vigabatrin, a small molecule that binds irreversibly to ABAT and inhibits the enzymatic activity, increased proliferation. In summary, we detected an accumulation of beta-alanine in breast cancer and an increase of beta-alanine and a down-regulation of ABAT in the more aggressive ER- subtype. The regulation of beta-alanine metabolism that underlies these changes is currently investigated in cell culture models. 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 4806. doi:1538-7445.AM2012-4806
Endoscopic Ultrasound in the Etiological Diagnosis of Idiopathic Pancreatitis
Authors: Qin Shan-Yu, Jiang Hai-Xing, Tan Zhi-Rou, Tang Guo-Du
Journal: Endoscopy (2011)

Aims: Recent new laboratory and technological advances have been able to shred the enigmatic veils of (Idiopathic Pancreatitis, IP) to a point wherein with extensive evaluation it is possible to reveal the etiology in 79%-80% of patients previously labeled as having idiopathic pancreatitis. More modern imaging investigations include, but are not limited to fine cut computerized tomography, endoscopic retrograde pancreatography, magnetic resonance pancreatography as well as endoscopic ultrasound.
Abstract 5331: CHK1 inhibition enhances chemosensitivity of p53 deficient osteosarcoma cells
Authors: Gufeng Xu, Hongmei Wang, Nino C. Rainusso, Ricardo J. Flores, Timothy Triche, Tsz-Kwong Man, Ching C. Lau
Journal: Cancer Research (2011)

Abstract Osteosarcoma is the most common malignant bone tumor in children. Using expression profiling, we have previously identified a 45-gene chemoresistance signature in osteosarcoma that can predict tumor response to neo-adjuvant chemotherapy. One of the signature genes is CHEK1, which was expressed significantly higher in osteosarcomas that respond poorly to neoadjuvant chemotherapy. CHEK1 encodes a Serine/threonine-protein kinase CHK1 that regulates both G2/M and S phases of the cell cycle mainly through phosphorylation of CDC25, and particularly controls the entry into mitosis. In this study, we used two independent short hairpin RNA (shRNA) constructs to knock-down CHEK1 expression in a p53-mutated osteosarcoma cell line 143B and a p53- wild type osteosarcoma cell line U2OS. The results show that the stably transduced CHEK1 knock-down 143B cells, but not U2OS cells, became more sensitive to both doxorubicin and cisplatin treatment relative to the parental or scrambled control cells. The results of the cytotoxicity assay were confirmed by clonogenic assay using 143B and U2OS stable transfectants. Using a CHK1 inhibitor UCN-01, we found that mutation status of p53 in different osteosarcoma cells lines correlated with their sensitivity to doxorubicin or cisplatin in the presence of UCN-01. Using flow cytometry, we also validated the activity of UCN-01 in abolishing the cell cycle arrest induced by doxorubicin or cisplatin treatment in 143B cells. In summary, our results confirm that CHEK1 expression is not only a potential biomarker for predicting chemoresistance in osteosarcoma, but also potentially represents a therapeutic target for overcoming chemoresistance in osteosarcoma with the use of small molecule CHK1 inhibitors. Further experiments involving in vivo orthotropic xenograft mouse model with both CHEK1 knock-down osteosarcoma cells and CHK1 inhibitors is underway. 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 5331. doi:10.1158/1538-7445.AM2011-5331
Endpiece: Medical statisticians
Authors: S. Senn
Journal: BMJ (1999)

Study designThe design of this study was a conventional randomised controlled trial in that all eligible patients were randomised.However, the participants were asked to state their preferred treatment before they knew of their allocation.A study of antenatal services showed that preferences can be an important determinant of outcome, 10 but we did not find any strong effect of preference on the outcome, although a much larger sample size would be needed to confidently exclude any modest interaction between preference and outcome. 8This information may be useful to clinicians in that it suggests that exercise classes are effective even in patients who are not highly motivated.Our trial design, of asking patients for their preferences at the outset, has substantial advantages over the usual patient preference design, in which costs and outcomes cannot be reliably controlled for confounding by preference. ConclusionsOur exercise programme did not seem to influence the intensity of pain but did affect the participants' ability to cope with the pain in the short term and even more so in the longer term.It used a cognitive-behavioural model, shifting the emphasis away from a disease model to a model of normal human behaviour, and with minimal extra training a physiotherapist can run it.Patients' preferences did not seem to influence the outcome.Contributors: JKM conceived the study, developed the protocol, obtained funding, designed and directed the trial, recruited general practitioners, and drafted the paper.DT advised on the organisation and collection of economic data, carried out statistical analysis of the costs, and helped to write the paper.SB-S coordinated the
Unique features of human movement control predicted by the leading joint hypothesis
Authors: Natalia Dounskaia
Journal: Behavioral and Brain Sciences (2012)

Abstract Vaesen suggests that motor control is not among the primary origins of the uniqueness of human tool use. However, recent findings show that cognitive processes involved in control of human limb movements may be much more sophisticated than it was believed previously. The sophistication of movement control may substantially contribute to the uniqueness of humans in tool use.