tbuckley/cabot-search huggingface dataset:
Association of Cytochrome P450 2C19 Genotype With the Antiplatelet Effect and Clinical Efficacy of Clopidogrel Therapy
Authors: Alan R. Shuldiner
Journal: JAMA (2009)

<h3>Context</h3>Clopidogrel therapy improves cardiovascular outcomes in patients with acute coronary syndromes and following percutaneous coronary intervention by inhibiting adenosine diphosphate (ADP)–dependent platelet activation. However, nonresponsiveness is widely recognized and is related to recurrent ischemic events.<h3>Objective</h3>To identify gene variants that influence clopidogrel response.<h3>Design, Setting, and Participants</h3>In the Pharmacogenomics of Antiplatelet Intervention (PAPI) Study (2006-2008), we administered clopidogrel for 7 days to 429 healthy Amish persons and measured response by ex vivo platelet aggregometry. A genome-wide association study was performed followed by genotyping the loss-of-function cytochrome P450 (CYP) 2C19*2 variant (rs4244285). Findings in the PAPI Study were extended by examining the relation of CYP2C19*2 genotype to platelet function and cardiovascular outcomes in an independent sample of 227 patients undergoing percutaneous coronary intervention.<h3>Main Outcome Measure</h3>ADP-stimulated platelet aggregation in response to clopidogrel treatment and cardiovascular events.<h3>Results</h3>Platelet response to clopidogrel was highly heritable (h<sup>2</sup> = 0.73; P &lt; .001). Thirteen single-nucleotide polymorphisms on chromosome 10q24 within the CYP2C18–CYP2C19–CYP2C9–CYP2C8 cluster were associated with diminished clopidogrel response, with a high degree of statistical significance (P = 1.5 × 10<sup>−13</sup> for rs12777823, additive model). The rs12777823 polymorphism was in strong linkage disequilibrium with the CYP2C19*2 variant, and was associated with diminished clopidogrel response, accounting for 12% of the variation in platelet aggregation to ADP (P = 4.3 × 10<sup>−11</sup>). The relation between CYP2C19*2 genotype and platelet aggregation was replicated in clopidogrel-treated patients undergoing coronary intervention (P = .02). Furthermore, patients with the CYP2C19*2 variant were more likely (20.9% vs 10.0%) to have a cardiovascular ischemic event or death during 1 year of follow-up (hazard ratio, 2.42; 95% confidence interval, 1.18-4.99; P = .02).<h3>Conclusion</h3>CYP2C19*2 genotype was associated with diminished platelet response to clopidogrel treatment and poorer cardiovascular outcomes.
A comparative study of the metabolic effort expended by horse riders during a jumping competition.
Authors: J A Gutiérrez Rincón, J Vives Turcó, I Muro Martínez, I Casas Vaqué
Journal: British Journal of Sports Medicine (1992)

The three main Olympic horse riding disciplines are dressage, jumping, and three-day eventing (including dressage, cross country and jumping). In the jumping discipline (obstacle race), the 'team' (horse rider) is judged under the different conditions that might take place in a varied run. The horse is expected to show power and ability; the rider must show riding skill and good physical condition. However, the different conditions encountered by the rider during competition (duration of event, continuous isometric working level, especially in the inferior trunk, lead us to consider the need for a rider to develop different metabolic pathways to meet the high energy requirements of the competition.
Dreams are made of memories, but maybe not for memory
Authors: Mark Blagrove, Perrine Ruby, Jean-Baptiste Eichenlaub
Journal: Behavioral and Brain Sciences (2013)

Llewellyn's claim that rapid eye movement (REM) dream imagery may be related to the processes involved in memory consolidation during sleep is plausible. However, whereas there is voluntary and deliberate intention behind the construction of images in the ancient art of memory (AAOM) method, there is a lack of intentionality in producing dream images. The memory for dreams is also fragile, and dependent on encoding once awake.
Cannabinoids Induce Cancer Cell Proliferation via Tumor Necrosis Factor α-Converting Enzyme (TACE/ADAM17)-Mediated Transactivation of the Epidermal Growth Factor Receptor
Authors: Stefan Hart, Oliver M. Fischer, Axel Ullrich
Journal: Cancer Research (2004)

Abstract Cannabinoids, the active components of marijuana and their endogenous counterparts were reported as useful analgetic agents to accompany primary cancer treatment by preventing nausea, vomiting, and pain and by stimulating appetite. Moreover, they have been shown to inhibit cell growth and to induce apoptosis in tumor cells. Here, we demonstrate that anandamide, Δ9-tetrahydrocannabinol (THC), HU-210, and Win55,212-2 promote mitogenic kinase signaling in cancer cells. Treatment of the glioblastoma cell line U373-MG and the lung carcinoma cell line NCI-H292 with nanomolar concentrations of THC led to accelerated cell proliferation that was completely dependent on metalloprotease and epidermal growth factor receptor (EGFR) activity. EGFR signal transactivation was identified as the mechanistic link between cannabinoid receptors and the activation of the mitogen-activated protein kinases extracellular signal-regulated kinase 1/2 as well as prosurvival protein kinase B (Akt/PKB) signaling. Depending on the cellular context, signal cross-communication was mediated by shedding of proAmphiregulin (proAR) and/or proHeparin-binding epidermal growth factor-like growth factor (proHB-EGF) by tumor necrosis factor α converting enzyme (TACE/ADAM17). Taken together, our data show that concentrations of THC comparable with those detected in the serum of patients after THC administration accelerate proliferation of cancer cells instead of apoptosis and thereby contribute to cancer progression in patients.
Ly-49-independent natural killer (NK) cell specificity revealed by NK cell clones derived from p53-deficient mice.
Authors: F M Karlhofer, M M Orihuela, W M Yokoyama
Journal: The Journal of Experimental Medicine (1995)

Natural killer (NK) cells are heterogeneous in their specificity and expression of cell surface molecules. In the mouse, the Ly-49A molecule is a primary determinant of NK cell specificity because of its ability to downregulate NK cell activation after physical interaction with target cell MHC class I molecules. Ly-49A is expressed on an NK cell subset, and it belongs to a family of highly related molecules that may similarly dictate major histocompatibility complex (MHC) class I-associated specificity of Ly-49A- NK cells. It is not known, however, whether murine NK cell specificity may occur independently of the Ly-49 family and target cell MHC class I molecules. Similar to the impact of cloned murine T cell lines on molecular description of T cell recognition, derivation of cloned murine NK cells should permit dissection of NK cell specificity but, to date, it has not been possible to produce such effector cells. In this study, we derived NK cell clones from mice that were homozygous for a mutation in the p53 tumor suppressor gene. The cloned cells displayed the molecular, cell surface, and functional phenotype of NK cells. Significantly, the NK cell clones displayed clonal differences in ability to kill a panel of murine tumor targets and did not lyse normal cells. Target lysis was unaffected by target cell MHC class I expression, and none of the clones expressed Ly-49A on the cell surface or transcripts for Ly-49 isoforms. Although consistent with the possibility that NK cell specificity for MHC class I molecules is mediated by the Ly-49 family of molecules, the results indicate that NK cell specificity also is regulated by a mechanism independent of target cell MHC class I and the Ly-49 family.
P262 Oramorph for breathlessness: in pursuit of guidelines and patient information for use in COPD
Authors: A. Williamson, L. Restrick, C. Potter, S. Purcell, S. Roberts, B. Coleman, M. Stern
Journal: Thorax (2011)

<h3>Introduction</h3> Breathlessness is the most common and frightening symptom in Chronic Obstructive Pulmonary Disease (COPD). Short-acting morphine (Oramorph) has traditionally been used to treat breathlessness in palliative care. Although used in COPD (Simon <i>et al</i>, 2010), there is no consensus/guidelines for prescribing and patients stigmatise morphine, associating it with dying or addiction. In this study, we assessed current prescribing practice, patient use and safety of Oramorph, to inform local prescribing guidelines and patient information. <h3>Method</h3> Case notes of patients who were prescribed Oramorph for breathlessness while having multidisciplinary COPD care between 2004 and 2011 were reviewed. The following were documented: patient demographics, disease severity (FEV<sub>1</sub>, MRC dyspnoea score, nebulisers, long term oxygen therapy (LTOT), domiciliary Non-Invasive Ventilation (NIV), social/healthcare support and palliative care referrals; Oramorph starting dosage, dosage range, increase in dosage, patient choice to continue, duration of and use of morphine sulphate slow release tablet (MST). <h3>Results</h3> 28 COPD patients prescribed Oramorph for breathlessness were identified (14 M), median (range) age 70 (52–83) years FEV<sub>1</sub> (mean±SD) 0.58±0.22, MRC dyspnoea score 4.6±0.49. 19/28 (68%) were on LTOT, 28/28 (100%) on nebulisers, 5/28 (17%) on domiciliary NIV, two current smokers, 10/28 (36%) lived alone, 27/28 (96%) had professional healthcare domiciliary visits, 8/28 (29%) had palliative care input. Starting, incremental and current dosing of Oramorph are shown in the Abstract P262 table 1. 25/28 (89%) patients chose to stay on Oramorph once started. Median (range) duration on Oramorph was 8 months (45 days–7.5 years). MST was added for breathlessness in three patients. 13/28 (46%) patients died; all were MRC 5 and starting Oramorph was not felt to be a contributing factor by the clinical team. Time to death after starting Oramorph was median (range) 7 months (68 days–2.6 years). Oramorph prescribing in COPD increased year-on-year (one patient in 2004 to 12 in 2010). <h3>Conclusion</h3> Oramorph prescribed by a respiratory team for breathlessness is safe in this group of patients. This study indicates that its effect is sustained despite low dosages with little requirement for incremental dosing over time. Guidelines for prescribing and patient information will be critical to ensure that patients are not denied this useful treatment of breathlessness.
An audit of first aid qualifications and knowledge among team officials in two English youth football leagues: a preliminary study
Authors: A Cunningham
Journal: British Journal of Sports Medicine (2002)

Objectives: To determine if youth football officials responsible for dealing with injuries have appropriate first aid qualifications and knowledge? Methods: Information was collected from two youth football leagues by questionnaire. First aiders were asked to provide details of their qualifications and their response from a list of alternatives to an injury scenario. Results: Fifty two of 86 respondents did not have a current first aid qualification. Only 12% and 38% respectively gave the correct response to the injury scenarios “player choking” and “player unconscious”. Health and injury records for the players were kept by 40% and 19% of teams. Written parental consent to emergency treatment was obtained by 30%. Conclusion: This preliminary study shows an obligation on teams who do not possess a qualified first aider to evaluate their legal and moral responsibilities to their players. The Football Association and Health and Safety Executive should produce a list of recommended equipment, facilities, and first aid qualified personnel to which teams should have access at games and training sessions. Providers of first aid training should reassess their teaching of the management of the choking and unconscious casualty.
Clinical Utility of Patient-Derived Xenografts to Determine Biomarkers of Prognosis and Map Resistance Pathways in <i>EGFR</i>-Mutant Lung Adenocarcinoma
Authors: Erin L. Stewart, Celine Mascaux, Nhu-An Pham, Shingo Sakashita, Jenna Sykes, Lucia Kim, Naoki Yanagawa, Ghassan Allo, Kota Ishizawa, Dennis Wang, Chang-Qi Zhu, Ming Li, Christine Ng, Ni Liu, Melania Pintilie, Petra Martin, Tom John, Igor Jurisica, Natasha B. Leighl, Benjamin G. Neel, Thomas K. Waddell, Frances A. Shepherd, Geoffrey Liu, Ming-Sound Tsao
Journal: Journal of Clinical Oncology (2015)

Although epidermal growth factor receptor (EGFR) -mutated adenocarcinomas initially have high response rates to EGFR tyrosine kinase inhibitors (TKIs), most patients eventually develop resistance. Patient-derived xenografts (PDXs) are considered preferred preclinical models to study the biology of patient tumors. EGFR-mutant PDX models may be valuable tools to study the biology of these tumors and to elucidate mechanisms of resistance to EGFR-targeted therapies.Surgically resected early-stage non-small-cell lung carcinoma (NSCLC) tumors were implanted into nonobese diabetic severe combined immune deficient (NOD-SCID) mice. EGFR TKI treatment was initiated at tumor volumes of 150 μL. Gene expression analysis was performed using a microarray platform.Of 33 lung adenocarcinomas with EGFR activating mutations, only 6 (18%) engrafted and could be propagated beyond passage one. Engraftment was associated with upregulation of genes involved in mitotic checkpoint and cell proliferation. A differentially expressed gene set between engrafting and nonengrafting patients could identify patients harboring EGFR-mutant tumor with significantly different prognoses in The Cancer Genome Atlas Lung Adenocarcinoma datasets. The PDXs included models with variable sensitivity to first- and second-generation EGFR TKIs and the monoclonal antibody cetuximab. All EGFR-mutant NSCLC PDXs studied closely recapitulated their corresponding patient tumor phenotype and clinical course, including response pattern to EGFR TKIs.PDX models closely recapitulate primary tumor biology and clinical outcome. They may serve as important laboratory models to investigate mechanisms of resistance to targeted therapies, and for preclinical testing of novel treatment strategies.
Effect of Ethidium Bromide on Transplanted Virus-Induced Tumor Cells2
Authors: V. J. Richardson, L. Vodinelich, A. Wilson, C. W. Potter
Journal: JNCI Journal of the National Cancer Institute (1976)

Ethidium bromide (2,3-diamino-5-ethyl-6-phenylphenanthridinium bromide) significantly inhibited the RNA-dependent DNA polymerase of types A and C particles isolated from transplanted adenovirus 12-induced tumors of CBA mice. It was also cytotoxic for an established in vitro line of adenovirus 12-induced tumor cells of CBA mice and caused cell death, inhibition of [3H]thymidine uptake, and a significant reduction of cells in metaphase. Ethidium bromide significantly inhibited the in vivo growth of transplanted adenovirus 12-induced tumor cells of CBA mice, simian virus 40-induced tumor cells of hamsters, and murine leukemia virus-induced lymphoma cells of BALB/c mice. The compound may have exerted the antitumor activity by selectively affecting oncornavirus in the tumor cells.
Pharmacologic Basis for the Enhanced Efficacy of Dutasteride against Prostatic Cancers
Authors: Yi Xu, Susan L. Dalrymple, Robyn E. Becker, Samuel R. Denmeade, John T. Isaacs
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Prostatic dihydrotestosterone (DHT) concentration is regulated by precursors from systemic circulation and prostatic enzymes of androgen metabolism, particularly 5α-reductases (i.e., SRD5A1 and SRD5A2). Therefore, the levels of expression SRD5A1 and SRD5A2 and the antiprostatic cancer growth response to finasteride, a selective SRD5A2 inhibitor, versus the dual SRD5A1 and SRD5A2 inhibitor, dutasteride, were compared. Experimental Design: Real-time PCR and enzymatic assays were used to determine the levels of SRD5A1 and SRD5A2 in normal versus malignant rat and human prostatic tissues. Rats bearing the Dunning R-3327H rat prostate cancer and nude mice bearing LNCaP or PC-3 human prostate cancer xenografts were used as model systems. Tissue levels of testosterone and DHT were determined using liquid chromatography-mass spectrometry. Results: Prostate cancer cells express undetectable to low levels of SRD5A2 but elevated levels of SRD5A1 activity compared with nonmalignant prostatic tissue. Daily oral treatment of rats with the SRD5A2 selective inhibitor, finasteride, reduces prostate weight and DHT content but did not inhibit R-3327H rat prostate cancer growth or DHT content in intact (i.e., noncastrated) male rats. In contrast, daily oral treatment with even a low 1 mg/kg/d dose of the dual SRD5A1 and SRD5A2 inhibitor, dutasteride, reduces both normal prostate and H tumor DHT content and weight in intact rats while elevating tissue testosterone. Daily oral treatment with finasteride significantly (P &amp;lt; 0.05) inhibits growth of LNCaP human prostate cancer xenografts in intact male nude mice, but this inhibition is not as great as that by equimolar oral dosing with dutasteride. This anticancer efficacy is not equivalent, however, to that produced by castration. Only combination of dutasteride and castration produces a greater tumor inhibition (P &amp;lt; 0.05) than castration monotherapy against androgen-responsive LNCaP cancers. In contrast, no response was induced by dutasteride in nude mice bearing androgen-independent PC-3 human prostatic cancer xenografts. Conclusions: These results document that testosterone is not as potent as DHT but does stimulate prostate cancer growth, thus combining castration with dutasteride enhances therapeutic efficacy.
Chorion Patterning: A Window into Gene Regulation and Drosophila Species’ Relatedness
Authors: Matthew G. Niepielko, Robert A. Marmion, Kenneth Kim, David Luor, Chelsea Ray, Nir Yakoby
Journal: Molecular Biology and Evolution (2013)

Changes in gene regulation are associated with the evolution of morphologies. However, the specific sequence information controlling gene expression is largely unknown and discovery is time and labor consuming. We use the intricate patterning of follicle cells to probe species’ relatedness in the absence of sequence information. We focus on one of the major families of genes that pattern the Drosophila eggshell, the Chorion protein (Cp). Systematically screening for the spatiotemporal patterning of all nine Cp genes in three species (Drosophila melanogaster, D. nebulosa, and D. willistoni), we found that most genes are expressed dynamically during mid and late stages of oogenesis. Applying an annotation code, we transformed the data into binary matrices that capture the complexity of gene expression. Gene patterning is sufficient to predict species’ relatedness, consistent with their phylogeny. Surprisingly, we found that expression domains of most genes are different among species, suggesting that Cp regulation is rapidly evolving. In addition, we found a morphological novelty along the dorsalmost side of the eggshell, the dorsal ridge. Our matrix analysis placed the dorsal ridge domain in a cluster of epidermal growth factor receptor associated domains, which was validated through genetic and chemical perturbations. Expression domains are regulated cooperatively or independently by signaling pathways, supporting that complex patterns are combinatorially assembled from simple domains.
Dysregulation of the IL-13 Receptor System. A Novel Pathomechanism in Pulmonary Arterial Hypertension
Authors: Matthias Hecker, Zbigniew Zasłona, Grażyna Kwapiszewska, Gero Niess, Anna Zakrzewicz, Eduard Hergenreider, Jochen Wilhelm, Leigh M. Marsh, Daniel Sedding, Walter Klepetko, Jürgen Lohmeyer, Stefanie Dimmeler, Werner Seeger, Norbert Weissmann, Ralph T. Schermuly, Nikolaus Kneidinger, Oliver Eickelberg, Rory E. Morty
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Idiopathic pulmonary arterial hypertension (IPAH) is characterized by medial hypertrophy due to pulmonary artery smooth muscle cell (paSMC) hyperplasia. Inflammation is proposed to play a role in vessel remodeling associated with IPAH. IL-13 is emerging as a regulator of tissue remodeling; however, the contribution of the IL-13 system to IPAH has not been assessed.The objective of this study was to assess the possible contribution of the IL-13 system to IPAH.Expression and localization of IL-13, and IL-13 receptors IL-4R, IL-13Rα1, and IL-13Rα2 were assessed by real-time reverse transcription-polymerase chain reaction, immunohistochemistry, and flow cytometry in lung tissue, paSMC, and microdissected vascular lesions from patients with IPAH, and in lung tissue from rodents with hypoxia- or monocrotaline-induced pulmonary hypertension. A whole-genome microarray analysis was used to study IL-13-regulated genes in paSMC.Pulmonary expression of the IL-13 decoy receptor IL-13Rα2 was up-regulated relative to that of the IL-13 signaling receptors IL-4R and IL-13Rα1 in patients with IPAH and in two animal models of IPAH. IL-13, signaling via STAT3 and STAT6, suppressed proliferation of paSMC by promoting G(0)/G(1) arrest. Whole-genome microarrays revealed that IL-13 suppressed endothelin-1 production by paSMC, suggesting that IL-13 controlled paSMC growth by regulating endothelin production. Ectopic expression of the il13ra2 gene resulted in partial loss of paSMC growth control by IL-13 and blunted IL-13 suppression of endothelin-1 production by paSMC, whereas small-interfering RNA knockdown of il13ra2 gene expression had the opposite effects.The IL-13 system is a novel regulator of paSMC growth. Dysregulation of IL-13 receptor expression in IPAH may partially underlie smooth muscle hypertrophy associated with pathological vascular remodeling in IPAH.
Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS
Authors: Mariely DeJesus-Hernandez, Ian R. Mackenzie, Bradley F. Boeve, Adam L. Boxer, Matt Baker, Nicola J. Rutherford, Alexandra M. Nicholson, NiCole A. Finch, Heather Flynn, Jennifer Adamson, Naomi Kouri, Aleksandra Wojtas, Pheth Sengdy, Ging-Yuek R. Hsiung, Anna Karydas, William W. Seeley, Keith A. Josephs, Giovanni Coppola, Daniel H. Geschwind, Zbigniew K. Wszolek, Howard Feldman, David S. Knopman, Ronald C. Petersen, Bruce L. Miller, Dennis W. Dickson, Kevin B. Boylan, Neill R. Graff-Radford, Rosa Rademakers
Journal: Neuron (2011)
Iron Homeostasis Regulates the Activity of the MicroRNA Pathway through Poly(C)-Binding Protein 2
Authors: Yujing Li, Li Lin, Zigang Li, Xuecheng Ye, Ke Xiong, Baikuntha Aryal, Zihui Xu, Zain Paroo, Qinghua Liu, Chuan He, Peng Jin
Journal: Cell Metabolism (2012)