tbuckley/cabot-search huggingface dataset:
Hallmarks of Aromatase Inhibitor Drug Resistance Revealed by Epigenetic Profiling in Breast Cancer
Authors: Maurice P.H.M. Jansen, Theo Knijnenburg, Esther A. Reijm, Iris Simon, Ron Kerkhoven, Marjolein Droog, Arno Velds, Steven van Laere, Luc Dirix, Xanthippi Alexi, John A. Foekens, Lodewyk Wessels, Sabine C. Linn, Els M.J.J. Berns, Wilbert Zwart
Journal: Cancer Research (2013)

Abstract Aromatase inhibitors are the major first-line treatment of estrogen receptor–positive breast cancer, but resistance to treatment is common. To date, no biomarkers have been validated clinically to guide subsequent therapy in these patients. In this study, we mapped the genome-wide chromatin-binding profiles of estrogen receptor α (ERα), along with the epigenetic modifications H3K4me3 and H3K27me3, that are responsible for determining gene transcription (n = 12). Differential binding patterns of ERα, H3K4me3, and H3K27me3 were enriched between patients with good or poor outcomes after aromatase inhibition. ERα and H3K27me3 patterns were validated in an additional independent set of breast cancer cases (n = 10). We coupled these patterns to array-based proximal gene expression and progression-free survival data derived from a further independent cohort of 72 aromatase inhibitor–treated patients. Through this approach, we determined that the ERα and H3K27me3 profiles predicted the treatment outcomes for first-line aromatase inhibitors. In contrast, the H3K4me3 pattern identified was not similarly informative. The classification potential of these genes was only partially preserved in a cohort of 101 patients who received first-line tamoxifen treatment, suggesting some treatment selectivity in patient classification. Cancer Res; 73(22); 6632–41. ©2013 AACR.
Noncanonical Activity of Seryl-tRNA Synthetase Is Involved in Vascular Development
Authors: Hajime Fukui, Ryuki Hanaoka, Atsuo Kawahara
Journal: Circulation Research (2009)

Vascular endothelial growth factor (Vegf) plays central roles in the establishment of stereotypic vascular patterning in vertebrates. However, it is not fully understood how the network of blood vessels is established and maintained during vascular development. A zebrafish ko095 mutant presented the disorganized vessels with abnormal branching of the established intersegmental vessels (ISVs) after 60 hours postfertilization. The gene responsible for ko095 encodes seryl-tRNA synthetase (Sars) with a nonsense mutation. The abnormal branching of ISVs in ko095 mutant was suppressed by the introduction of either wild-type Sars or a mutant Sars (T429A) lacking the enzymatic activity that catalyzes aminoacylation of transfer RNA for serine (canonical activity), suggesting that the abnormal branching is attributable to the loss of function of Sars besides its canonical activity. We further found the increased expression of vegfa in ko095 mutant at 72 hours postfertilization, which was also reversed by the introduction of Sars (T429A). Furthermore, the abnormal branching of ISVs in the mutant was suppressed by knockdown of vegfa or vegfr2 ( kdra and kdrb ). Knockdown of vegfc or vegfr3 rescued the abnormal ISV branching in ko095 mutant. These results suggest that the abnormal ISV branching in ko095 mutant is caused by the activated Vegfa-Vegfr2 signal and requires the Vegfc-Vegfr3 signal, because the latter is needed for general angiogenesis. Hence, we conclude that noncanonical activity of Sars is involved in vascular development presumably by modulating the expression of vegfa .
Breast Cancer Screening Using Small-Angle X-ray Scattering Analysis of Human Hair
Authors: P Meyer, R Goergl, J W Botz, P Fratzl
Journal: JNCI Journal of the National Cancer Institute (2000)

available only at specialized centers. We, therefore, decided to repeat the investigations with a recently developed small-angle x-ray scattering (SAXS) system (10) (Nanostar System; Bruker AXS GmbH, Karlsruhe, Germany). The SAXS system offers high reliability and fast measuring time without the requirement for synchrotron radiation. It consists of an ordinary sealed-tube x-ray generator powering a standard finefocus Cu tube. The collimation system, a pair of cross-coupled multilayer mirrors (Goebel mirrors), produces a nearly perfect parallel beam. Measurements are done in the laboratory by a highresolution SAXS camera with a pinhole system. Samples are measured in transmission, and the scattering signal is detected at a distance of 65 cm from the specimen by a high-sensitivity, two
Anaphylactic reaction to young garlic
Authors: Aj Pérez‐pimiento, M Santaolalla, S De Paz, B Fernández‐parra, A. R Domínguez‐lázaro, I Moneo
Journal: Allergy (1999)

Background: Garlic is well known to cause contact dermatitis and asthma. However, it is a very rare cause of food allergy. We present the case of a 23‐year‐old woman with previous history of allergy to pollen and dried fruit, and food‐dependent, exercise‐induced anaphylaxis for which no specific food could be identified as responsible, who experienced an anaphylactic reaction after eating young garlic. Methods: Skin prick tests and specific IgE immunoassay with several pollens and foods were performed, as well as the prick‐prick test with young garlic and SDS–PAGE followed by immunoblotting IgE to young garlic and other Liliaceae species, mustard, sesame, parsley, celery, hazelnut, almond, and pollen of birch and mugwort. Results: Skin prick tests and specific IgE were mainly positive for grass, plane tree, and mugwort pollen; peanut; hazelnut; walnut; almond; and mustard. Prick‐prick tests with young garlic and garlic were positive. Total IgE was 113 U/ml. SDS–PAGE immunoblotting showed IgE‐binding bands at 12 kDa to young garlic, garlic, onion, and leek extracts. Similar bands could also be detected with mugwort pollen and hazelnut extract. Conclusions: We describe IgE‐mediated reaction to young garlic in a patient sensitized to pollen and dried fruit.
Outcomes at 2 Years of Age after Repeat Doses of Antenatal Corticosteroids
Authors: Caroline A. Crowther, Lex W. Doyle, Ross R. Haslam, Janet E. Hiller, Jane E. Harding, Jeffrey S. Robinson
Journal: New England Journal of Medicine (2007)

We previously reported the results of a randomized, controlled trial showing that repeat doses of antenatal corticosteroids reduced the risk of respiratory distress syndrome and serious neonatal morbidity. However, data have not been available regarding longer-term effects of this treatment.Women who had received an initial course of corticosteroid treatment 7 or more days previously were randomly assigned to receive an intramuscular injection of corticosteroid (11.4 mg of betamethasone) or saline placebo; the dose was repeated weekly if the mother was still considered to be at risk for preterm delivery and the duration of gestation was less than 32 weeks. We assessed survival free of major neurosensory disability and body size of the children at 2 years of corrected age.Of the 1085 children who were alive at 2 years of age, 1047 (96.5%) were seen for assessment (521 exposed to repeat-corticosteroid treatment and 526 exposed to placebo). The rate of survival free of major disability was similar in the repeat-corticosteroid and placebo groups (84.4% and 81.0%, respectively; adjusted relative risk, 1.04, 95% confidence interval, 0.98 to 1.10; adjusted P=0.20). There were no significant differences between the groups in body size, blood pressure, use of health services, respiratory morbidity, or child behavior scores, although children exposed to repeat doses of corticosteroids were more likely than those exposed to placebo to warrant assessment for attention problems (P=0.04).Administration of repeat doses of antenatal corticosteroids reduces neonatal morbidity without changing either survival free of major neurosensory disability or body size at 2 years of age. (Current Controlled Trials number, ISRCTN48656428 [controlled-trials.com].).
Gastro-oesophageal reflux and aspiration in patients with advanced lung disease
Authors: M P Sweet, M G Patti, C Hoopes, S R Hays, J A Golden
Journal: Thorax (2009)

Numerous small observational studies have shown that gastro-oesophageal reflux is prevalent among patients with advanced lung disease. The fundamental concern is that reflux is a risk factor for recurrent microaspiration, which may cause lung injury. For example, in lung transplant patients, a molecular marker of aspiration was a risk factor for the bronchiolitis obliterans syndrome in one study. To date, however, there are no large prospective studies measuring the impact of aspiration on clinical outcomes. The major obstacle limiting the study of reflux and aspiration in patients with advanced lung disease is the absence of a reliable diagnostic tool. Proximal oesophageal acid detection by pH monitoring is the only widely available measure of aspiration risk. Impedance monitoring may be a superior measure of aspiration risk as it measures both acid and non-acid reflux episodes. Molecular markers of aspiration, such as pepsin or bile salts in the bronchoalveolar lavage or exhaled breath condensate, may be the optimal diagnostic tests, but they are not currently available outside the research setting. Larger observational studies are needed to determine the following: (1) the clinical significance of aspiration in patients with advanced lung disease and in patients who have had lung transplantation and (2) the diagnostic test that best predicts adverse outcomes.
"Destemming" Cancer Stem Cells
Authors: R. P. Hill, R. Perris
Journal: JNCI Journal of the National Cancer Institute (2007)

Cancer stem cells have been variously defined as cells within a cancer that have the exclusive ability to self-renew and to differentiate into the heterogeneous lineages of cancer cells that comprise the tumor. Interest in cancer stem cells is currently high, arising from recent reports identifying cell surface markers that can be used to sort such cells from primary human tumors. However, use of the term cancer stem cell may be misleading. A better term might be cancer-initiating cells because it remains to be demonstrated that cancer stem cells have the properties that define normal stem cells, including multipotency and the ability to undergo asymmetric and symmetric divisions. Many properties of cancer stem cells remain unclear, particularly the stability of their phenotype. These uncertainties must be considered in the development and testing of compounds targeted against putative cancer stem cells. Tumors apparently contain very few cancer stem cells, so that when tests of compounds targeted to such cells are designed, short-term response trials may not be informative and long-term trials must be planned, particularly if the drugs could also kill normal stem cells.
Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2
Authors: Kazuya Takahashi, Christian D.P. Rochford, Harald Neumann
Journal: The Journal of Experimental Medicine (2005)

Elimination of apoptotic neurons without inflammation is crucial for brain tissue homeostasis, but the molecular mechanism has not been firmly established. Triggering receptor expressed on myeloid cells-2 (TREM2) is a recently identified innate immune receptor. Here, we show expression of TREM2 in microglia. TREM2 stimulation induced DAP12 phosphorylation, extracellular signal–regulated kinase phosphorylation, and cytoskeleton reorganization and increased phagocytosis. Knockdown of TREM2 in microglia inhibited phagocytosis of apoptotic neurons and increased gene transcription of tumor necrosis factor α and nitric oxide synthase-2, whereas overexpression of TREM2 increased phagocytosis and decreased microglial proinflammatory responses. Thus, TREM2 deficiency results in impaired clearance of apoptotic neurons and inflammation that might be responsible for the brain degeneration observed in patients with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy/Nasu-Hakola disease.
Low Levels of Phosphorylated Epidermal Growth Factor Receptor in Nonmalignant and Malignant Prostate Tissue Predict Favorable Outcome in Prostate Cancer Patients
Authors: Peter Hammarsten, Amar Karalija, Andreas Josefsson, Stina Häggström Rudolfsson, Pernilla Wikström, Lars Egevad, Torvald Granfors, Pär Stattin, Anders Bergh
Journal: Clinical Cancer Research (2010)

To explore if the expression of phosphorylated epidermal growth factor receptor (pEGFR) in nonmalignant and malignant prostate tissue is a potential prognostic marker for outcome in prostate cancer patients.We used formalin-fixed tissues obtained through the transurethral resection of the prostate from 259 patients diagnosed with prostate cancer after the transurethral resection of the prostate, and patients were then followed with watchful waiting. Tissue microarrays of nonmalignant and malignant prostate tissue were stained with an antibody against pEGFR. The staining pattern was scored and related to clinicopathologic parameters and to outcome.Low phosphorylation of EGFR in prostate epithelial cells, both in the tumor and surprisingly also in the surrounding nonmalignant tissue, was associated with significantly longer cancer-specific survival in prostate cancer patients. This association remained significant when Gleason score and local tumor stage were added together with pEGFR to a Cox regression model. Tumor epithelial pEGFR immunoreactivity was significantly correlated to tumor cell proliferation, tumor vascular density, and nonmalignant epithelial pEGFR immunoreactivity. Patients with metastases had significantly higher immunoreactivity for tumor and nonmalignant epithelial pEGFR compared with patients without metastases.Low pEGFR immunoreactivity is associated with the favorable prognosis in prostate cancer patients and may provide information about which patients with Gleason score 6 and 7 tumors that will survive their disease even without treatment. Changes in the nonmalignant tissue adjacent to prostate tumors give prognostic information.
EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis
Authors: M J L Peters, D P M Symmons, D McCarey, B A C Dijkmans, P Nicola, T K Kvien, I B McInnes, H Haentzschel, M A Gonzalez-Gay, S Provan, A Semb, P Sidiropoulos, G Kitas, Y M Smulders, M Soubrier, Z Szekanecz, N Sattar, M T Nurmohamed
Journal: Annals of the Rheumatic Diseases (2009)

Objectives: To develop evidence-based EULAR recommendations for cardiovascular (CV) risk management in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Methods: A multidisciplinary expert committee was convened as a task force of the EULAR Standing Committee for Clinical Affairs (ESCCA), comprising 18 members including rheumatologists, cardiologists, internists and epidemiologists, representing nine European countries. Problem areas and related keywords for systematic literature research were identified. A systematic literature research was performed using MedLine, Embase and the Cochrane library through to May 2008. Based on this literature review and in accordance with the EULAR’s “standardised operating procedures”, the multidisciplinary steering committee formulated evidence-based and expert opinion-based recommendations for CV risk screening and management in patients with inflammatory arthritis. Results: Annual CV risk assessment using national guidelines is recommended for all patients with RA and should be considered for all patients with AS and PsA. Any CV risk factors identified should be managed according to local guidelines. If no local guidelines are available, CV risk management should be carried out according to the SCORE function. In addition to appropriate CV risk management, aggressive suppression of the inflammatory process is recommended to further lower the CV risk. Conclusions: Ten recommendations were made for CV risk management in patients with RA, AS and PsA. The strength of the recommendations differed between RA on the one hand, and AS and PsA, on the other, as evidence for an increased CV risk is most compelling for RA.
Cardiotoxic effect with convulsions in terfenadine overdose.
Authors: A J Davies, V Harindra, A McEwan, R R Ghose
Journal: BMJ (1989)

shown abnormalities ranging from mild portal inflammation to centrizonal collapse with bridging.The course has been suggestive ofa hypersensitivity reaction with a shorter period to develop- ment ofabnormal liver function after re-exposure to the drug.Ours is the first case with typical pathological features of chronic active hepatitis.The evidence strongly implicated cimetidine.In- advertent re-exposure to the drug caused rapid recurrence of jaundice and abnormal liver function values, and withdrawal of cimetidine and treat- ment with prednisone for two months returned these values to normal, although repeat biopsy still showed evidence of chronic active hepatitis.Preexisting chronic active hepatitis exacerbated by cimetidine is unlikely in the absence of other recognised causes of chronic active hepatitis.This case adds to the slowly accumulating evidence implicating cimetidine as a rare but definite hepatotoxin.The low incidence makes monitoring of liver function values unlikely to be cost effective, but when clinical hepatitis occurs cimetidine must be considered a potential villain.
Mechanism of the Lower Esophageal Sphincter Relaxation ACTION OF PROSTAGLANDIN E1 AND THEOPHYLLINE
Authors: Raj K. Goyal, Satish Rattan
Journal: Journal of Clinical Investigation (1973)

The intravenous injection of prostaglandin E(1) (PGE(1)) causes a dose-dependent relaxation of the lower esophageal sphincter (LES) in the intact, lightly anesthetized opossum. The action of PGE(1) is not inhibited by the drugs that produce muscarinic or nicotinic cholinergic antagonism or alpha and beta adrenergic antagonism in the doses that inhibited the action of respective agonists. Moreover, this action is not affected by exogenous gastrin pentapeptide. The action of PGE(1) on the LES is mimicked by isoproterenol, theophylline ethylenediamine, and dibutyryl cyclic AMP. Both theophylline, a phosphodiesterase inhibitor, and isoproterenol, an adenyl cyclase stimulator, added to the action of PGE(1). On the other hand, adenyl cyclase inhibitor nicotinic acid, as well as phosphodiesterase stimulator, imidazole inhibited its action. Further, both nicotinic acid and imidazole inhibited the degree of LES relaxation produced by esophageal distension. These studies suggest that intracellular cyclic AMP may act as the "second messenger" in the regulation of the lower esophageal sphincter relaxation.
Activation of the NF-κB pathway as a mechanism of alcohol enhanced progression and metastasis of human hepatocellular carcinoma
Authors: Fei Wang, Jin-Lian Yang, Ke-ke Yu, Mei Xu, You-zhi Xu, Li Chen, Yan-min Lu, Hao-shu Fang, Xin-yi Wang, Zhong-qian Hu, Fei-fei Li, Lixin Kan, Jia Luo, Si-Ying Wang
Journal: Molecular Cancer (2015)

Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is the third leading cause of cancer-related death in human. Alcohol is a known risk factor for HCC. However it is still unclear whether and how alcohol enhances the progression and metastasis of existing HCC. We first retrospectively investigated 52 HCC patients (24 alcohol-drinkers and 28 non-drinkers), and found a positive correlation between alcohol consumption and advanced Tumor-Node-Metastasis (TNM) stages, higher vessel invasion and poorer prognosis. In vitro and in vivo experiments further indicated that alcohol promoted the progression and migration/invasion of HCC. Specifically, in a 3-D tumor/endothelial co-culture system, we found that alcohol enhanced the migration/invasion of HepG2 cells and increased tumor angiogenesis. Consistently, higher expression of VEGF, MCP-1 and NF-κB was observed in HCC tissues of alcohol-drinkers. Alcohol induced the accumulation of intracellular reactive oxygen species (ROS) and the activation of NF-κB signaling in HepG2 cells. Conversely, blockage of alcohol-mediated ROS accumulation and NF-κB signaling inhibited alcohol-induced expression of VEGF and MCP-1, the tumor growth, angiogenesis and metastasis. This study suggested that chronic moderate alcohol consumption may promote the progression and metastasis of HCC; the oncogenic effect may be at least partially mediated by the ROS accumulation and NF-ĸB-dependent VEGF and MCP-1 up-regulation.
Oxidation of the Endogenous Cannabinoid Arachidonoyl Ethanolamide by the Cytochrome P450 Monooxygenases: Physiological and Pharmacological Implications
Authors: Natasha T. Snider, Vyvyca J. Walker, Paul F. Hollenberg
Journal: Pharmacological Reviews (2010)

Arachidonoyl ethanolamide (anandamide) is an endogenous amide of arachidonic acid and an important signaling mediator of the endocannabinoid system. Given its numerous roles in maintaining normal physiological function and modulating pathophysiological responses throughout the body, the endocannabinoid system is an important pharmacological target amenable to manipulation directly by cannabinoid receptor ligands or indirectly by drugs that alter endocannabinoid synthesis and inactivation. The latter approach has the possible advantage of more selectivity, thus there is the potential for fewer untoward effects like those that are traditionally associated with cannabinoid receptor ligands. In that regard, inhibitors of the principal inactivating enzyme for anandamide, fatty acid amide hydrolase (FAAH), are currently in development for the treatment of pain and inflammation. However, several pathways involved in anandamide synthesis, metabolism, and inactivation all need to be taken into account when evaluating the effects of FAAH inhibitors and similar agents in preclinical models and assessing their clinical potential. Anandamide undergoes oxidation by several human cytochrome P450 (P450) enzymes, including CYP3A4, CYP4F2, CYP4X1, and the highly polymorphic CYP2D6, forming numerous structurally diverse lipids, which are likely to have important physiological roles, as evidenced by the demonstration that a P450-derived epoxide of anandamide is a potent agonist for the cannabinoid receptor 2. The focus of this review is to emphasize the need for a better understanding of the P450-mediated pathways of the metabolism of anandamide, because these are likely to be important in mediating endocannabinoid signaling as well as the pharmacological responses to endocannabinoid-targeting drugs.