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Adverse outcome pathway

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https://www.readbyqxmd.com/read/28548702/p16-loss-and-e2f-cell-cycle-deregulation-in-infant-posterior-fossa-ependymoma
#1
Seth C Lummus, Andrew M Donson, Katherine Gowan, Kenneth L Jones, Rajeev Vibhakar, Nicholas K Foreman, B K Kleinschmidt-DeMasters
BACKGROUND: Posterior fossa (PF) ependymomas (EPNs) in infants less than 1 year of age (iEPN-PF) have a poorer clinical outcome than EPNs in older children. While radiation therapy is the standard of care for the latter, it is withheld in infants to avoid neurotoxicity to immature brain. It is unknown whether the adverse outcome in iEPN-PFs is due to treatment differences or aggressive biology. We examined this question using molecular profiling. METHODS: Six anaplastic iEPN-PFs were subjected to transcriptomic analysis and FISH for p16 loss and gains of 1q, and compared with anaplastic PF EPNs from older children...
May 26, 2017: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/28543973/advancing-the-adverse-outcome-pathway-framework-an-international-horizon-scanning-approach
#2
Carlie A LaLone, Gerald T Ankley, Scott E Belanger, Michelle R Embry, Geoff Hodges, Dries Knapen, Sharon Munn, Edward J Perkins, Murray A Rudd, Daniel L Villeneuve, Maurice Whelan, Catherine Willett, Xiaowei Zhang, Markus Hecker
Our ability to conduct whole-organism toxicity tests to understand chemical safety has been outpaced by the synthesis of new chemicals for a wide variety of commercial applications. As a result, scientists and risk assessors are turning to mechanistically based studies to increase efficiencies in chemical risk assessment and making greater use of in vitro and in silico methods to evaluate potential environmental and human health hazards. In this context, the adverse outcome pathway (AOP) framework has gained traction in regulatory science because it offers an efficient and effective means for capturing available knowledge describing the linkage between mechanistic data and the apical toxicity end points required for regulatory assessments...
June 2017: Environmental Toxicology and Chemistry
https://www.readbyqxmd.com/read/28543848/non-animal-assessment-of-skin-sensitization-hazard-is-an-integrated-testing-strategy-needed-and-if-so-what-should-be-integrated
#3
REVIEW
David W Roberts, Grace Patlewicz
There is an expectation that to meet regulatory requirements, and avoid or minimize animal testing, integrated approaches to testing and assessment will be needed that rely on assays representing key events (KEs) in the skin sensitization adverse outcome pathway. Three non-animal assays have been formally validated and regulatory adopted: the direct peptide reactivity assay (DPRA), the KeratinoSens™ assay and the human cell line activation test (h-CLAT). There have been many efforts to develop integrated approaches to testing and assessment with the "two out of three" approach attracting much attention...
May 24, 2017: Journal of Applied Toxicology: JAT
https://www.readbyqxmd.com/read/28541519/reduced-sleep-during-social-isolation-leads-to-cellular-stress-and-induction-of-the-unfolded-protein-response-upr
#4
Marishka K Brown, Ewa Strus, Nirinjini Naidoo
Study Objectives: Social isolation has a multitude of negative consequences on human health including the ability to endure challenges to the immune system, sleep amount and efficiency, and general morbidity and mortality. These adverse health outcomes are conserved in other social species. In the fruit fly Drosophila melanogaster, social isolation leads to increased aggression, impaired memory and reduced amounts of daytime sleep. There is a correlation between molecules affected by social isolation and those implicated in sleep in Drosophila...
May 25, 2017: Sleep
https://www.readbyqxmd.com/read/28536863/chemical-exposure-and-infant-leukaemia-development-of-an-adverse-outcome-pathway-aop-for-aetiology-and-risk-assessment-research
#5
REVIEW
Olavi Pelkonen, Andrea Terron, Antonio F Hernandez, Pablo Menendez, Susanne Hougaard Bennekou
Infant leukaemia (<1 year old) is a rare disease of an in utero origin at an early phase of foetal development. Rearrangements of the mixed-lineage leukaemia (MLL) gene producing abnormal fusion proteins are the most frequent genetic/molecular findings in infant B cell-acute lymphoblastic leukaemia. In small epidemiological studies, mother/foetus exposures to some chemicals including pesticides have been associated with infant leukaemia; however, the strength of evidence and power of these studies are weak at best...
May 23, 2017: Archives of Toxicology
https://www.readbyqxmd.com/read/28534511/stromal-derived-igf2-promotes-colon-cancer-progression-via-paracrine-and-autocrine-mechanisms
#6
C Unger, N Kramer, D Unterleuthner, M Scherzer, A Burian, A Rudisch, M Stadler, M Schlederer, D Lenhardt, A Riedl, S Walter, A Wernitznig, L Kenner, M Hengstschläger, J Schüler, W Sommergruber, H Dolznig
The insulin-like growth factor (IGF)2/IGF1 receptor (IGF1R) signaling axis has an important role in intestinal carcinogenesis and overexpression of IGF2 is an accepted risk factor for colorectal cancer (CRC) development. Genetic amplifications and loss of imprinting contribute to the upregulation of IGF2, but insufficiently explain the extent of IGF2 expression in a subset of patients. Here, we show that IGF2 was specifically induced in the tumor stroma of CRC and identified cancer-associated fibroblasts (CAFs) as the major source...
May 22, 2017: Oncogene
https://www.readbyqxmd.com/read/28533818/a-novel-bcr-abl1-fusion-gene-with-genetic-heterogeneity-indicates-a-good-prognosis-in-a-chronic-myeloid-leukemia-case
#7
Fen Zhou, Runming Jin, Yu Hu, Heng Mei
BACKGROUND: Chronic myelogenous leukemia (CML) is a pluripotent hematopoietic stem cell disorder caused by the fusion of the BCR and ABL1 genes. Quantitative RT-PCR (qRT-PCR) is a routinely performed screening technique to identify BCR-ABL1 fusion genes, but a limitation of this method is its inability to recognize novel fusions that have not been previously characterized. Next-generation sequencing (NGS) is an effective and sensitive detection method for the determination of novel BCR-ABL1 fusion genes as well as previously characterized ones...
2017: Molecular Cytogenetics
https://www.readbyqxmd.com/read/28530537/aspergillus-fischeri-mediated-biosynthesis-of-gold-nanoparticles-and-their-beneficially-comparative-effect-on-normal-and-cancer-cell-lines
#8
Kangkana Banerjee, Ravishankar Rai Vittal
Background Along with the intensified use of metal nanoparticles, growing concern of their adverse outcome on human health has also expanded, indicating that this work is an integral part of nanobioscience study. Objective The aim of this study was to evaluate varied effect of biosynthesized gold nanoparticles (AuNPs) on normal and cancerous mammalian cells. Methods AuNP synthesized and characterized by different characterization methods, here are produced by specifically isolated Aspergillus species, which is hardly explored in precious scientific findings...
May 22, 2017: Pharmaceutical Nanotechnology
https://www.readbyqxmd.com/read/28529068/adverse-outcome-pathways-application-to-enhance-mechanistic-understanding-of-neurotoxicity
#9
REVIEW
Anna Bal-Price, M E Meek
Recent developments have prompted the transition of empirically based testing of late stage toxicity in animals for a range of different endpoints including neurotoxicity to more efficient and predictive mechanistically based approaches with greater emphasis on measurable key events early in the progression of disease. The adverse outcome pathway (AOP) has been proposed as a simplified organizational construct to contribute to this transition by linking molecular initiating events and earlier (more predictive) key events at lower levels of biological organization to disease outcomes...
May 18, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28527947/embryonic-vascular-disruption-adverse-outcomes-linking-high-throughput-signaling-signatures-with-functional-consequences
#10
Robert G Ellis-Hutchings, Raja S Settivari, Alene T McCoy, Nicole Kleinstreuer, Jill Franzosa, Thomas B Knudsen, Edward W Carney
Embryonic vascular disruption is an important adverse outcome pathway (AOP) as chemical disruption of cardiovascular development induces broad prenatal defects. High throughput screening (HTS) assays aid AOP development although linking in vitro data to in vivo apical endpoints remains challenging. This study evaluated two anti-angiogenic agents, 5HPP-33 and TNP-470, across the ToxCastDB HTS assay platform and anchored the results to complex in vitro functional assays: the rat aortic explant assay (AEA), rat whole embryo culture (WEC), and the zebrafish embryotoxicity (ZET) assay...
May 17, 2017: Reproductive Toxicology
https://www.readbyqxmd.com/read/28526328/acrylamide-induced-neurotoxicity-in-primary-astrocytes-and-microglia-roles-of-the-nrf2-are-and-nf-%C3%AE%C2%BAb-pathways
#11
Mengyao Zhao, Fu Sheng Lewis Wang, Xiaosong Hu, Fang Chen, Hing Man Chan
Acrylamide (AA) is a common food contaminant formed during food heat processing that has neurotoxic effects. We hypothesize that AA induces oxidative stress in astrocytes and microglia, leading to neurotoxicity. Oxidative status, translocation of Nrf2 and NF-κB, and related down-stream targets were measured in primary astrocytes and microglia obtained from BALB/c mice. The results showed that AA increased reactive oxygen species (ROS) formation and reduced glutathione levels, causing successive events associated with oxidative stress, including 4-hydroxynonenal and 8-hydroxy-2-deoxyguanosine adduct formation, in both cell types...
May 16, 2017: Food and Chemical Toxicology
https://www.readbyqxmd.com/read/28525648/the-role-of-omics-in-the-application-of-adverse-outcome-pathways-for-chemical-risk-assessment
#12
Erica K Brockmeier, Geoff Hodges, Thomas H Hutchinson, Emma Butler, Markus Hecker, Knut Erik Tollefsen, Natalia Garcia-Reyero, Peter Kille, Dörthe Becker, Kevin Chipman, John Colbourne, Timothy W Collette, Andrew Cossins, Mark Cronin, Peter Graystock, Steve Gutsell, Dries Knapen, Ioanna Katsiadaki, Anke Lange, Stuart Marshall, Stewart F Owen, Edward J Perkins, Stewart Plaistow, Anthony Schroeder, Daisy Taylor, Mark Viant, Gerald Ankley, Francesco Falciani
In conjunction with the second International Environmental Omics Symposium (iEOS) conference, held at the University of Liverpool (UK) in September 2014, a workshop was held to bring together experts in toxicology and regulatory science from academia, government and industry. The purpose of the workshop was to review the specific roles that high-content omics datasets (e.g., transcriptomics, metabolomics, lipidomics, and proteomics) can hold within the adverse outcome pathway (AOP) framework for supporting ecological and human health risk assessments...
May 19, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28521238/transcriptomic-approach-for-assessment-of-the-impact-on-microalga-and-macrophyte-of-in-situ-exposure-in-river-sites-contaminated-by-chlor-alkali-plant-effluents
#13
Perrine Dranguet, Claudia Cosio, Séverine Le Faucheur, Rebecca Beauvais-Flück, Aline Freiburghaus, Isabelle A M Worms, Brice Petit, Natacha Civic, Mylène Docquier, Vera I Slaveykova
Water quality degradation is a worldwide problem, but risk evaluation of chronic pollution in-situ is still a challenge. The present study aimed to evaluate the potential of transcriptomic analyses in representative aquatic primary producers to assess the impact of environmental pollution in-situ: the microalga Chlamydomonas reinhardtii and the macrophyte Elodea nuttallii were exposed 2 h in the Babeni Reservoir of the Olt River impacted by chlor-alkali plant effluent release resulting in increased concentrations of Hg and NaCl in receiving water...
May 11, 2017: Water Research
https://www.readbyqxmd.com/read/28515464/systems-immunology-of-diabetes-tuberculosis-comorbidity-reveals-signatures-of-disease-complications
#14
Cesar A Prada-Medina, Kiyoshi F Fukutani, Nathella Pavan Kumar, Leonardo Gil-Santana, Subash Babu, Flávio Lichtenstein, Kim West, Shanmugam Sivakumar, Pradeep A Menon, Vijay Viswanathan, Bruno B Andrade, Helder I Nakaya, Hardy Kornfeld
Comorbid diabetes mellitus (DM) increases tuberculosis (TB) risk and adverse outcomes but the pathological interactions between DM and TB remain incompletely understood. We performed an integrative analysis of whole blood gene expression and plasma analytes, comparing South Indian TB patients with and without DM to diabetic and non-diabetic controls without TB. Luminex assay of plasma cytokines and growth factors delineated a distinct biosignature in comorbid TBDM in this cohort. Transcriptional profiling revealed elements in common with published TB signatures from cohorts that excluded DM...
May 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28512159/employing-extracellular-volume-cardiovascular-magnetic-resonance-measures-of-myocardial-fibrosis-to-foster-novel-therapeutics
#15
Erik B Schelbert, Hani N Sabbah, Javed Butler, Mihai Gheorghiade
Quantifying myocardial fibrosis (MF) with myocardial extracellular volume measures acquired during cardiovascular magnetic resonance promises to transform clinical care by advancing pathophysiologic understanding and fostering novel therapeutics. Extracellular volume quantifies MF by measuring the extracellular compartment depicted by the myocardial uptake of contrast relative to plasma. MF is a key domain of dysfunctional but viable myocardium among others (eg, microvascular dysfunction and cardiomyocyte/mitochondrial dysfunction)...
June 2017: Circulation. Cardiovascular Imaging
https://www.readbyqxmd.com/read/28507730/application-of-the-adverse-outcome-pathway-aop-concept-to-structure-the-available-in-vivo-and-in-vitro-mechanistic-data-for-allergic-sensitization-to-food-proteins
#16
REVIEW
Jolanda H M van Bilsen, Edyta Sienkiewicz-Szłapka, Daniel Lozano-Ojalvo, Linette E M Willemsen, Celia M Antunes, Elena Molina, Joost J Smit, Barbara Wróblewska, Harry J Wichers, Edward F Knol, Gregory S Ladics, Raymond H H Pieters, Sandra Denery-Papini, Yvonne M Vissers, Simona L Bavaro, Colette Larré, Kitty C M Verhoeckx, Erwin L Roggen
BACKGROUND: The introduction of whole new foods in a population may lead to sensitization and food allergy. This constitutes a potential public health problem and a challenge to risk assessors and managers as the existing understanding of the pathophysiological processes and the currently available biological tools for prediction of the risk for food allergy development and the severity of the reaction are not sufficient. There is a substantial body of in vivo and in vitro data describing molecular and cellular events potentially involved in food sensitization...
2017: Clinical and Translational Allergy
https://www.readbyqxmd.com/read/28500823/aflatoxin-exposure-during-pregnancy-maternal-anemia-and-adverse-birth-outcomes
#17
Laura E Smith, Andrew J Prendergast, Paul C Turner, Jean H Humphrey, Rebecca J Stoltzfus
AbstractPregnant women and their developing fetuses are vulnerable to multiple environmental insults, including exposure to aflatoxin, a mycotoxin that may contaminate as much as 25% of the world food supply. We reviewed and integrated findings from studies of aflatoxin exposure during pregnancy and evaluated potential links to adverse pregnancy outcomes. We identified 27 studies (10 human cross-sectional studies and 17 animal studies) assessing the relationship between aflatoxin exposure and adverse birth outcomes or anemia...
April 2017: American Journal of Tropical Medicine and Hygiene
https://www.readbyqxmd.com/read/28494686/clinical-pharmacology-efficacy-and-safety-of-selexipag-for-the-treatment-of-pulmonary-arterial-hypertension
#18
Shirin Bruderer, Noémie Hurst, Tatiana Remenova, Jasper Dingemanse
Selexipag is the first oral, non-prostanoid, selective prostacyclin receptor (IP receptor) agonist, approved for the long-term treatment of pulmonary arterial hypertension (PAH) in adult patients. Areas covered: This article reviews the clinical pharmacology, efficacy, and safety of selexipag in the treatment of PAH. Expert opinion: Selexipag is the first oral drug that selectively targets the prostacyclin pathway, and has evidence of long-term efficacy and safety. In the global phase 3 study GRIPHON (NCT01106014) in PAH patients, selexipag significantly reduced the risk of the primary composite outcome of morbidity/mortality (M/M)...
June 2017: Expert Opinion on Drug Safety
https://www.readbyqxmd.com/read/28490812/hdac3-regulates-dnmt1-expression-in-multiple-myeloma-therapeutic-implications
#19
T Harada, H Ohguchi, Y Grondin, S Kikuchi, M Sagawa, Y-T Tai, R Mazitschek, T Hideshima, K C Anderson
Epigenetic signaling pathways are implicated in tumorigenesis and therefore histone deacetylases (HDACs) represent novel therapeutic targets for cancers including multiple myeloma (MM). Although non-selective HDAC inhibitors show anti-MM activities, unfavorable side effects limit their clinical efficacy. Isoform- and/or class-selective HDAC inhibition offers the possibility to maintain clinical activity while avoiding adverse events attendant to broad non-selective HDAC inhibition. We have previously reported that HDAC3 inhibition, either by genetic knockdown or selective inhibitor BG45, abrogates MM cell proliferation...
May 11, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28490533/the-tryptophan-kynurenine-pathway-systemic-inflammation-and-long-term-outcome-after-kidney-transplantation
#20
Laura V de Vries, Isidor Minovic, Casper Fm Franssen, Martijn van Faassen, Jan-Stephan F Sanders, Stefan P Berger, Gerjan Navis, Ido P Kema, Stephan Jl Bakker
BACKGROUND: Tryptophan is metabolized along the kynurenine pathway, initially to kynurenine, and subsequently to cytotoxic 3-hydroxykynurenine. There is increasing interest in this pathway, because of its pro-inflammatory nature, and drugs interfering in it receive increasing attention. We aimed to investigate whether serum and urinary parameters of the tryptophan-kynurenine pathway, and particularly cytotoxic 3-hydroxykynurenine, are associated with systemic inflammation and long-term outcome in renal transplant recipients (RTR)...
May 10, 2017: American Journal of Physiology. Renal Physiology
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