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https://www.readbyqxmd.com/read/28202629/improving-the-in-silico-assessment-of-proarrhythmia-risk-by-combining-herg-human-ether-%C3%A3-go-go-related-gene-channel-drug-binding-kinetics-and-multichannel-pharmacology
#1
Zhihua Li, Sara Dutta, Jiansong Sheng, Phu N Tran, Wendy Wu, Kelly Chang, Thembi Mdluli, David G Strauss, Thomas Colatsky
BACKGROUND: The current proarrhythmia safety testing paradigm, although highly efficient in preventing new torsadogenic drugs from entering the market, has important limitations that can restrict the development and use of valuable new therapeutics. The CiPA (Comprehensive in vitro Proarrhythmia Assay) proposes to overcome these limitations by evaluating drug effects on multiple cardiac ion channels in vitro and using these data in a predictive in silico model of the adult human ventricular myocyte...
February 2017: Circulation. Arrhythmia and Electrophysiology
https://www.readbyqxmd.com/read/28192183/measuring-kinetics-and-potency-of-herg-block-for-cipa
#2
Monique J Windley, Najah Abi-Gerges, Bernard Fermini, Jules C Hancox, Jamie I Vandenberg, Adam P Hill
INTRODUCTION: The Comprehensive in vitro Proarrhythmic Assay (CiPA) aims to update current cardiac safety testing to better evaluate arrhythmic risk. A central theme of CiPA is the use of in silico approaches to risk prediction incorporating models of drug binding to hERG. To parameterize these models, accurate in vitro measurement of potency and kinetics of block is required. The Ion Channel Working Group was tasked with: i) selecting a protocol that could measure kinetics of block and was easily implementable on automated platforms for future rollout in industry and ii) acquiring a reference dataset using the standardized protocol...
February 10, 2017: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/28192073/recurrent-and-novel-mutations-in-the-ntrk1-gene-lead-to-rare-congenital-insensitivity-to-pain-with-anhidrosis-in-two-chinese-patients
#3
Fang Lv, Xiao-Jie Xu, Yu-Wen Song, Lu-Jiao Li, Ou Wang, Yan Jiang, Wei-Bo Xia, Xiao-Ping Xing, Peng Gao, Mei Li
BACKGROUND: Congenital insensitivity to pain with anhidrosis (CIPA) is an extremely rare autosomal recessive autonomic and sensory neuropathy. CIPA is associated with various mutations in NTRK1. CASES: Two unrelated Chinese patients presented separately with symptoms of insensitivity to pain, inability to sweat, repeated painless fractures, and Charcot arthropathy were recruited. Both of them were clinically diagnosed with CIPA. Increased serum bone resorption marker (β-CTX) levels and decreased BMD were observed in both patients...
February 10, 2017: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/28186716/cipa-and-cipb-as-scaffolds-to-organize-proteins-into-crystalline-inclusions
#4
Yang Wang, Ralf Heermann, Kirsten Jung
Natural and synthetic scaffolds support enzyme organization in complexes, and they regulate their function and activity. Here we report that CipA and CipB, two small proteins that form protein crystalline inclusions (PCIs) in the cytoplasm of Photorhabdus luminescens, can be utilized as scaffolds to efficiently incorporate exogenous proteins into PCIs. We demonstrate that Cip-tagged GFP is assembled into fluorescent PCIs in P. luminescens and that in Escherichia coli Cip scaffolds can organize GFP or/and LacZ into bioactive PCIs, which could easily be isolated for in vitro catalysis...
February 10, 2017: ACS Synthetic Biology
https://www.readbyqxmd.com/read/28177573/novel-ntrk1-mutations-associated-with-congenital-insensitivity-to-pain-with-anhidrosis-verified-by-functional-studies
#5
Tai-Seung Nam, Wenting Li, Somy Yoon, Gwang Hyeon Eom, Myeong-Kyu Kim, Sung Taek Jung, Seok-Yong Choi
Congenital insensitivity to pain with anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV (HSAN-IV), features loss of pain sensation, decreased or absent sweating (anhidrosis), recurrent episodes of unexplained fever, self-mutilating behavior and variable mental retardation. Mutations in neurotrophic receptor tyrosine kinase 1 (NTRK1) have been reported to be associated with CIPA. We identified four novel NTRK1 mutations in six Korean patients from four unrelated families. Of the four mutations, we demonstrated using a splicing assay that IVS14+3A>T causes aberrant splicing of NTRK1 mRNA, leading to introduction of a premature termination codon...
February 8, 2017: Journal of the Peripheral Nervous System: JPNS
https://www.readbyqxmd.com/read/28159788/revisiting-the-regulation-of-the-primary-scaffoldin-gene-in-clostridium-thermocellum
#6
Lizett Ortiz de Ora, Iván Muñoz-Gutiérrez, Edward A Bayer, Yuval Shoham, Raphael Lamed, Ilya Borovok
: Cellulosomes are considered to be one of the most efficient systems for degradation of plant cell-wall polysaccharides. The central cellulosome component comprises a large, noncatalytic, protein subunit called scaffoldin. Multiple saccharolytic enzymes are incorporated into the scaffoldins via specific high-affinity cohesin-dockerin interactions. Recently, the regulation of genes encoding certain cellulosomal components by multiple RNA polymerase alternative σ(I) factors has been demonstrated in Clostridium (Ruminiclostridium) thermocellum In the present report, we provide experimental evidence demonstrating that the C...
February 3, 2017: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/28010774/recombinant-cellulolytic-or-xylanolytic-complex-comprising-the-full-length-scaffolding-protein-rjcipa-and-cellulase-rjcel5b-or-xylanase-rjxyn10c-of-ruminiclostridium-josui
#7
Taku Orita, Makiko Sakka, Tetsuya Kimura, Kazuo Sakka
Three cellulosomal subunits of Ruminiclostridium josui, the full-length scaffolding protein CipA (RjCipA), a cellulase Cel5B (RjCel5B) and a xylanase Xyn10C (RjXyn10C), were successfully produced by Escherichia coli recombinant clones. RjCel5B and RjXyn10C were characterized as an endoglucanase and an endoxylanase, respectively. RjCipA, RjCel5B and Xyn10C adsorbed to microcrystalline cellulose (Funacel) and rice straw powder. Interaction between RjCel5B and RjCipA, and RjXyn10C and RjCipA were confirmed by qualitative assays...
February 2017: Enzyme and Microbial Technology
https://www.readbyqxmd.com/read/27772781/congenital-insensitivity-to-pain-with-anhidrosis-a-report-of-two-siblings-with-a-novel-mutation-in-trka-ntrk1-gene-in-a-saudi-family
#8
Hussein Algahtani, Muhammad Imran Naseer, Mohammad Al-Qahtani, Shireen Abubakr Abdulrahman, Faisal Boker, Bader Shirah
Congenital insensitivity to pain with anhidrosis (CIPA) or hereditary sensory and autonomic neuropathy type IV (HSAN type IV) is an extremely rare autosomal recessive disorder with an estimated incidence of 1 in 25,000. It was first described in 1963, and since then several case reports and review articles have been published. In this article, we report two brothers with clinical features of CIPA, who presented with recurrent episodes of hyperthermia, anhidrosis, profound loss of pain sensitivity, and unconscious self-mutilation of fingers, lip and tongue...
November 15, 2016: Journal of the Neurological Sciences
https://www.readbyqxmd.com/read/27772759/congenital-insensitivity-to-pain-and-anhidrosis-case-report-and-review-of-findings-along-neuro-immune-axis-in-the-disorder
#9
Aditi Vian Varma, Lori McBride, Michael Marble, Ann Tilton
Congenital insensitivity to pain and anhidrosis (CIPA) is one of the hereditary autonomic and sensory neuropathies. Typically presenting in infancy, it manifests as hyperpyrexia from defects in sweating (autonomic) and self-mutilating injuries from pain insensitivity (sensory). CIPA being rare in North America, diagnosis is often missed due to variable presentation. Subsequent management of its complications is therefore delayed. We report an unusual presentation in a 2-year-old girl with preexisting diagnosis of CIPA who was evaluated for bilateral upper extremity paresis of insidious onset...
November 15, 2016: Journal of the Neurological Sciences
https://www.readbyqxmd.com/read/27718759/early-drug-development-assessment-of-proarrhythmic-risk-and-cardiovascular-safety
#10
Robert M Lester, Joy Olbertz
hERG assays and thorough ECG trials have been mandated since 2005 to evaluate the QT interval and potential proarrhythmic risk of new chemical entities. The high cost of these studies and the shortcomings inherent in these binary and limited approaches to drug evaluation have prompted regulators to search for more cost effective and mechanistic paradigms to assess drug liability as exemplified by the CiPA initiative and the exposure response ICH E14(R3) guidance document. Areas covered: This review profiles the changing regulatory landscape as it pertains to early drug development and outlines the analyses that can be performed to characterize preclinical and early clinical cardiovascular risk...
December 2016: Expert Review of Clinical Pharmacology
https://www.readbyqxmd.com/read/27701120/comprehensive-translational-assessment-of-human-induced-pluripotent-stem-cell-derived-cardiomyocytes-for-evaluating-drug-induced-arrhythmias
#11
Ksenia Blinova, Jayna Stohlman, Jose Vicente, Dulciana Chan, Lars Johannesen, Maria P Hortigon-Vinagre, Victor Zamora, Godfrey Smith, William J Crumb, Li Pang, Beverly Lyn-Cook, James Ross, Mathew Brock, Stacie Chvatal, Daniel Millard, Loriano Galeotti, Norman Stockbridge, David G Strauss
Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) hold promise for assessment of drug-induced arrhythmias and are being considered for use under the comprehensive in vitro proarrhythmia assay (CiPA). We studied the effects of 26 drugs and 3 drug combinations on 2 commercially available iPSC-CM types using high-throughput voltage-sensitive dye and microelectrode-array assays being studied for the CiPA initiative and compared the results with clinical QT prolongation and torsade de pointes (TdP) risk...
January 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/27641943/integrating-cardiomyocytes-from-human-pluripotent-stem-cells-in-safety-pharmacology-has-the-time-come
#12
Luca Sala, Milena Bellin, Christine L Mummery
Cardiotoxicity is a severe side effect of drugs that induce structural or electrophysiological changes in heart muscle cells. As a result, the heart undergoes failure and potentially lethal arrhythmias. It is still a major reason for drug failure in preclinical and clinical phases of drug discovery. Current methods for predicting cardiotoxicity are based on guidelines which combine electrophysiological analysis of cell lines expressing ion channels ectopically in vitro with animal models and clinical trials...
September 19, 2016: British Journal of Pharmacology
https://www.readbyqxmd.com/read/27637569/orthopaedic-manifestations-of-congenital-indifference-to-pain-with-anhidrosis-hereditary-sensory-and-autonomic-neuropathy-type-iv
#13
Babar Kayani, Mathew David Sewell, Johnson Platinum, Andre Olivier, Timothy W R Briggs, Deborah M Eastwood
BACKGROUND: Congenital indifference to pain with anhidrosis (CIPA) is a rare hereditary neuropathy, which is associated with defective sensation to noxious stimuli and autonomic dysfunction. The objective of the study was to report on the orthopaedic manifestations of this condition and provide an evidence-based approach for management. METHODS: Retrospective review of 14 consecutive patients with CIPA referred to a single tertiary centre. Mean age of diagnosis was 2...
September 6, 2016: European Journal of Paediatric Neurology: EJPN
https://www.readbyqxmd.com/read/27551041/mutations-in-trka-causing-congenital-insensitivity-to-pain-with-anhidrosis-cipa-induce-misfolding-aggregation-and-mutation-dependent-neurodegeneration-by-dysfunction-of-the-autophagic-flux
#14
María Luisa Franco, Cristina Melero, Esther Sarasola, Paloma Acebo, Alfonso Luque, Isabel Calatayud-Baselga, María García-Barcina, Marçal Vilar
Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive disorder characterized by insensitivity to noxious stimuli and variable intellectual disability (ID) due to mutations in the NTRK1 gene encoding the NGF receptor TrkA. To get an insight in the effect of NTRK1 mutations in the cognitive phenotype we biochemically characterized three TrkA mutations identified in children diagnosed of CIPA with variable ID. These mutations are located in different domains of the protein; L213P in the extracellular domain, Δ736 in the kinase domain, and C300stop in the extracellular domain, a new mutation causing CIPA diagnosed in a Spanish teenager...
October 7, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27524478/evolving-regulatory-paradigm-for-proarrhythmic-risk-assessment-for-new-drugs
#15
Jose Vicente, Norman Stockbridge, David G Strauss
Fourteen drugs were removed from the market worldwide because their potential to cause torsade de pointes (torsade), a potentially fatal ventricular arrhythmia. The observation that most drugs that cause torsade block the potassium channel encoded by the human ether-à-go-go related gene (hERG) and prolong the heart rate corrected QT interval (QTc) on the ECG, led to a focus on screening new drugs for their potential to block the hERG potassium channel and prolong QTc. This has been a successful strategy keeping torsadogenic drugs off the market, but has resulted in drugs being dropped from development, sometimes inappropriately...
November 2016: Journal of Electrocardiology
https://www.readbyqxmd.com/read/27282641/the-comprehensive-in-vitro-proarrhythmia-assay-cipa-initiative-update-on-progress
#16
Thomas Colatsky, Bernard Fermini, Gary Gintant, Jennifer B Pierson, Philip Sager, Yuko Sekino, David G Strauss, Norman Stockbridge
The implementation of the ICH S7B and E14 guidelines has been successful in preventing the introduction of potentially torsadogenic drugs to the market, but it has also unduly constrained drug development by focusing on hERG block and QT prolongation as essential determinants of proarrhythmia risk. The Comprehensive in Vitro Proarrhythmia Assay (CiPA) initiative was established to develop a new paradigm for assessing proarrhythmic risk, building on the emergence of new technologies and an expanded understanding of torsadogenic mechanisms beyond hERG block...
September 2016: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/27282640/multi-parametric-assessment-of-cardiomyocyte-excitation-contraction-coupling-using-impedance-and-field-potential-recording-a-tool-for-cardiac-safety-assessment
#17
Xiaoyu Zhang, Liang Guo, Haoyu Zeng, Stephen L White, Michael Furniss, Bharathi Balasubramanian, Edward Lis, Armando Lagrutta, Frederick Sannajust, Li Leyna Zhao, Biao Xi, Xiaobo Wang, Myrtle Davis, Yama A Abassi
INTRODUCTION: The ICH S7B guidelines recommend that all new chemical entities should be subjected to hERG repolarization screening due to its association with life-threatening "Torsades de Pointes" (TdP) arrhythmia. However, it has become evident that not all hERG channel inhibitors result in TdP and not all compounds that induce QT prolongation and TdP necessarily inhibit hERG. In order to address the limitations of the S7B/E14 guidelines, the FDA through a public/private partnership initiated the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative to examine the possible modification and refinement of the ICH E14/S7B guidelines...
September 2016: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/27235787/human-ex-vivo-action-potential-model-for-pro-arrhythmia-risk-assessment
#18
Guy Page, Phachareeya Ratchada, Yannick Miron, Guido Steiner, Andre Ghetti, Paul E Miller, Jack A Reynolds, Ken Wang, Andrea Greiter-Wilke, Liudmila Polonchuk, Martin Traebert, Gary A Gintant, Najah Abi-Gerges
While current S7B/E14 guidelines have succeeded in protecting patients from QT-prolonging drugs, the absence of a predictive paradigm identifying pro-arrhythmic risks has limited the development of valuable drug programs. We investigated if a human ex-vivo action potential (AP)-based model could provide a more predictive approach for assessing pro-arrhythmic risk in man. Human ventricular trabeculae from ethically consented organ donors were used to evaluate the effects of dofetilide, d,l-sotalol, quinidine, paracetamol and verapamil on AP duration (APD) and recognized pro-arrhythmia predictors (short-term variability of APD at 90% repolarization (STV(APD90)), triangulation (ADP90-APD30) and incidence of early afterdepolarizations at 1 and 2Hz to quantitatively identify the pro-arrhythmic risk...
September 2016: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/27233533/comprehensive-in-vitro-proarrhythmia-assay-cipa-pending-issues-for-successful-validation-and-implementation
#19
Icilio Cavero, Jean-Michel Guillon, Veronique Ballet, Mike Clements, Jean-Frédéric Gerbeau, Henry Holzgrefe
INTRODUCTION: The Comprehensive in vitro Proarrhythmia Assay (CiPA) is a nonclinical Safety Pharmacology paradigm for discovering electrophysiological mechanisms that are likely to confer proarrhythmic liability to drug candidates intended for human use. TOPICS COVERED: Key talks delivered at the 'CiPA on my mind' session, held during the 2015 Annual Meeting of the Safety Pharmacology Society (SPS), are summarized. Issues and potential solutions relating to crucial constituents [e...
September 2016: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/27184445/cardiotoxicity-screening-with-simultaneous-optogenetic-pacing-voltage-imaging-and-calcium-imaging
#20
Graham T Dempsey, Khuram W Chaudhary, Nicholas Atwater, Cuong Nguyen, Barry S Brown, John D McNeish, Adam E Cohen, Joel M Kralj
INTRODUCTION: The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative seeks an in vitro test to accurately predict clinical Torsades de Pointes (TdP). We developed a cardiotoxicity assay incorporating simultaneous measurement of the action potential (AP) waveform and Ca(2+) transient (CT) in human iPSC-derived cardiomyocytes (CMs). Concurrent optogenetic pacing provided a well-controlled electrophysiological background. METHODS: We used the Optopatch platform for all-optical electrophysiology (Hochbaum et al...
September 2016: Journal of Pharmacological and Toxicological Methods
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