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Article ; Online: RARG S427L attenuates the DNA repair response to doxorubicin in induced pluripotent stem cell-derived cardiomyocytes.

Huang, Haojun / Christidi, Effimia / Shafaattalab, Sanam / Davis, Margot K / Tibbits, Glen F / Brunham, Liam R

2022 Volume 17, Issue 4, Page(s) 756–765

Abstract: Doxorubicin is a commonly used chemotherapeutic drug, but its use is limited by doxorubicin-induced cardiotoxicity (DIC), which can lead to irreversible heart failure and death. A missense variant rs2229774 (p.S427L) in the retinoic acid receptor gamma ( ... ...

Abstract	Doxorubicin is a commonly used chemotherapeutic drug, but its use is limited by doxorubicin-induced cardiotoxicity (DIC), which can lead to irreversible heart failure and death. A missense variant rs2229774 (p.S427L) in the retinoic acid receptor gamma (RARG) gene is associated with increased susceptibility to DIC, but the precise mechanism underlying this association is incompletely understood. We performed molecular dynamic simulations to determine the effect of this variant on RARG structure and then validated these predictions using CRISPR-Cas9-genome-edited, induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). We found that this variant leads to reduced activation of its target genes in response to doxorubicin, including gene pathways involved in DNA repair and consequently an inability to mediate DNA repair after exposure to doxorubicin. Our findings establish a role of RARG p.S427L in attenuating DNA repair in DIC and provide insight into the pathogenesis of this cardiotoxic effect.
MeSH term(s)	Antibiotics, Antineoplastic/pharmacology ; Cardiotoxicity ; DNA Repair ; Doxorubicin/pharmacology ; Humans ; Induced Pluripotent Stem Cells ; Myocytes, Cardiac/metabolism
Chemical Substances	Antibiotics, Antineoplastic ; Doxorubicin (80168379AG)
Language	English
Publishing date	2022-03-31
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2720528-9
ISSN	2213-6711 ; 2213-6711
ISSN (online)	2213-6711
ISSN	2213-6711
DOI	10.1016/j.stemcr.2022.03.002
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: A perspective on Notch signalling in progression and arrhythmogenesis in familial hypertrophic and dilated cardiomyopathies.

Langa, Paulina / Shafaattalab, Sanam / Goldspink, Paul H / Wolska, Beata M / Fernandes, Aurelia A / Tibbits, Glen F / Solaro, R John

Philosophical transactions of the Royal Society of London. Series B, Biological sciences

2023 Volume 378, Issue 1879, Page(s) 20220176

Abstract: In this perspective, we discussed emerging data indicating a role for Notch signalling in inherited disorders of the heart failure with focus on hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) linked to variants of genes encoding ... ...

Abstract	In this perspective, we discussed emerging data indicating a role for Notch signalling in inherited disorders of the heart failure with focus on hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) linked to variants of genes encoding mutant proteins of the sarcomere. We recently reported an upregulation of elements in the Notch signalling cascade in cardiomyocytes derived from human inducible pluripotent stem cells expressing a TNNT2 variant encoding cardiac troponin T (cTnT-I79N
MeSH term(s)	Humans ; Cardiomyopathy, Dilated/genetics ; Cardiomyopathy, Dilated/metabolism ; Cardiomyopathy, Hypertrophic/genetics ; Troponin T/genetics ; Troponin T/metabolism ; Cardiomyopathies ; Hypertrophy ; Mutation
Chemical Substances	Troponin T
Language	English
Publishing date	2023-05-01
Publishing country	England
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	208382-6
ISSN	1471-2970 ; 0080-4622 ; 0264-3839 ; 0962-8436
ISSN (online)	1471-2970
ISSN	0080-4622 ; 0264-3839 ; 0962-8436
DOI	10.1098/rstb.2022.0176
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Article: hiPSC-derived cardiomyocytes as a model to study the role of small-conductance Ca

Babini, Hosna / Jiménez-Sábado, Verónica / Stogova, Ekaterina / Arslanova, Alia / Butt, Mariam / Dababneh, Saif / Asghari, Parisa / Moore, Edwin D W / Claydon, Thomas W / Chiamvimonvat, Nipavan / Hove-Madsen, Leif / Tibbits, Glen F

Frontiers in cell and developmental biology

2024 Volume 12, Page(s) 1298007

Abstract: Atrial fibrillation (AF), the most common arrhythmia, has been associated with different electrophysiological, molecular, and structural alterations in atrial cardiomyocytes. Therefore, more studies are required to elucidate the genetic and molecular ... ...

Abstract	Atrial fibrillation (AF), the most common arrhythmia, has been associated with different electrophysiological, molecular, and structural alterations in atrial cardiomyocytes. Therefore, more studies are required to elucidate the genetic and molecular basis of AF. Various genome-wide association studies (GWAS) have strongly associated different single nucleotide polymorphisms (SNPs) with AF. One of these GWAS identified the rs13376333 risk SNP as the most significant one from the 1q21 chromosomal region. The rs13376333 risk SNP is intronic to the
Language	English
Publishing date	2024-01-18
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2024.1298007
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Article: Investigating inherited arrhythmias using hiPSC-derived cardiomyocytes

Arslanova, Alia / Shafaattalab, Sanam / Lin, Eric / Barszczewski, Tiffany / Hove-Madsen, Leif / Tibbits, Glen F.

Methods. 2021 June 23,

2021

Abstract: Fundamental to the functional behavior of cardiac muscle is that the cardiomyocytes are integrated as a functional syncytium. Disrupted electrical activity in the cardiac tissue can lead to serious complications including cardiac arrhythmias. Therefore, ... ...

Abstract	Fundamental to the functional behavior of cardiac muscle is that the cardiomyocytes are integrated as a functional syncytium. Disrupted electrical activity in the cardiac tissue can lead to serious complications including cardiac arrhythmias. Therefore, it is important to study electrophysiological properties of the cardiac tissue.With advancements in stem cell research, protocols for the production of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been established, providing great potential in modelling cardiac arrhythmias and drug testing. The hiPSC-CM model can be used in conjunction with electrophysiology-based platforms to examine the electrical activity of the cardiac tissue. Techniques for determining the myocardial electrical activity include multielectrode arrays (MEAs), optical mapping (OM), and patch clamping. These techniques provide critical approaches to investigate cardiac electrical abnormalities that underlie arrhythmias.
Keywords	cardiomyocytes ; drugs ; electrophysiology ; giant cells ; humans ; models ; stem cells
Language	English
Dates of publication	2021-0623
Publishing place	Elsevier Inc.
Document type	Article
Note	Pre-press version
ZDB-ID	1066584-5
ISSN	1095-9130 ; 1046-2023
ISSN (online)	1095-9130
ISSN	1046-2023
DOI	10.1016/j.ymeth.2021.06.015
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Article ; Online: Investigating inherited arrhythmias using hiPSC-derived cardiomyocytes.

Arslanova, Alia / Shafaattalab, Sanam / Lin, Eric / Barszczewski, Tiffany / Hove-Madsen, Leif / Tibbits, Glen F

Methods (San Diego, Calif.)

2021 Volume 203, Page(s) 542–557

Abstract	Fundamental to the functional behavior of cardiac muscle is that the cardiomyocytes are integrated as a functional syncytium. Disrupted electrical activity in the cardiac tissue can lead to serious complications including cardiac arrhythmias. Therefore, it is important to study electrophysiological properties of the cardiac tissue. With advancements in stem cell research, protocols for the production of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been established, providing great potential in modelling cardiac arrhythmias and drug testing. The hiPSC-CM model can be used in conjunction with electrophysiology-based platforms to examine the electrical activity of the cardiac tissue. Techniques for determining the myocardial electrical activity include multielectrode arrays (MEAs), optical mapping (OM), and patch clamping. These techniques provide critical approaches to investigate cardiac electrical abnormalities that underlie arrhythmias.
MeSH term(s)	Action Potentials/physiology ; Arrhythmias, Cardiac/genetics ; Cells, Cultured ; Electrophysiological Phenomena ; Humans ; Induced Pluripotent Stem Cells/physiology ; Myocytes, Cardiac/physiology
Language	English
Publishing date	2021-06-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	1066584-5
ISSN	1095-9130 ; 1046-2023
ISSN (online)	1095-9130
ISSN	1046-2023
DOI	10.1016/j.ymeth.2021.06.015
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Article: Utility of Zebrafish Models of Acquired and Inherited Long QT Syndrome.

Simpson, Kyle E / Venkateshappa, Ravichandra / Pang, Zhao Kai / Faizi, Shoaib / Tibbits, Glen F / Claydon, Tom W

Frontiers in physiology

2021 Volume 11, Page(s) 624129

Abstract: Long-QT Syndrome (LQTS) is a cardiac electrical disorder, distinguished by irregular heart rates and sudden death. Accounting for ∼40% of cases, LQTS Type 2 (LQTS2), is caused by defects in the Kv11.1 (hERG) potassium channel that is critical for cardiac ...

Abstract	Long-QT Syndrome (LQTS) is a cardiac electrical disorder, distinguished by irregular heart rates and sudden death. Accounting for ∼40% of cases, LQTS Type 2 (LQTS2), is caused by defects in the Kv11.1 (hERG) potassium channel that is critical for cardiac repolarization. Drug block of hERG channels or dysfunctional channel variants can result in acquired or inherited LQTS2, respectively, which are typified by delayed repolarization and predisposition to lethal arrhythmia. As such, there is significant interest in clear identification of drugs and channel variants that produce clinically meaningful perturbation of hERG channel function. While toxicological screening of hERG channels, and phenotypic assessment of inherited channel variants in heterologous systems is now commonplace, affordable, efficient, and insightful whole organ models for acquired and inherited LQTS2 are lacking. Recent work has shown that zebrafish provide a viable
Language	English
Publishing date	2021-01-15
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2564217-0
ISSN	1664-042X
ISSN	1664-042X
DOI	10.3389/fphys.2020.624129
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Article: Atrial-specific hiPSC-derived cardiomyocytes in drug discovery and disease modeling

Gharanei, Mayel / Shafaattalab, Sanam / Sangha, Sarabjit / Gunawan, Marvin / Laksman, Zachary / Hove-Madsen, Leif / Tibbits, Glen F.

Methods. 2021 June 12,

2021

Abstract: The discovery and application of human-induced pluripotent stem cells (hiPSCs) have been instrumental in the investigation of the pathophysiology of cardiovascular diseases. Patient-specific hiPSCs can now be generated, genome-edited, and subsequently ... ...

Abstract	The discovery and application of human-induced pluripotent stem cells (hiPSCs) have been instrumental in the investigation of the pathophysiology of cardiovascular diseases. Patient-specific hiPSCs can now be generated, genome-edited, and subsequently differentiated into various cell types and used for regenerative medicine, disease modeling, drug testing, toxicity screening, and 3D tissue generation. Modulation of the retinoic acid signaling pathway has been shown to direct cardiomyocyte differentiation towards an atrial lineage. A variety of studies have successfully differentiated patient-specific atrial cardiac myocytes (hiPSC-aCM) and atrial engineered heart tissue (aEHT) that express atrial specific genes (e.g., sarcolipin and ANP) and exhibit atrial electrophysiological and contractility profiles. Identification of protocols to differentiate atrial cells from patients with atrial fibrillation and other inherited diseases or creating disease models using genetic mutation studies has shed light on the mechanisms of atrial-specific diseases and identified the efficacy of atrial-selective pharmacological compounds. hiPSC-aCMs and aEHTs can be used in drug discovery and drug screening studies to investigate the efficacy of atrial selective drugs on atrial fibrillation models. Furthermore, hiPSC-aCMs can be effective tools in studying the mechanism, pathophysiology and treatment options of atrial fibrillation and its genetic underpinnings. The main limitation of using hiPSC-CMs is their immature phenotype compared to adult CMs. A wide range of approaches and protocols are used by various laboratories to optimize and enhance CM maturation, including electrical stimulation, culture time, biophysical cues and changes in metabolic factors.
Keywords	adults ; atrial fibrillation ; cardiomyocytes ; drugs ; electrical treatment ; electrophysiology ; medicine ; mutation ; pathophysiology ; phenotype ; retinoic acid ; toxicity
Language	English
Dates of publication	2021-0612
Publishing place	Elsevier Inc.
Document type	Article
Note	Pre-press version
ZDB-ID	1066584-5
ISSN	1095-9130 ; 1046-2023
ISSN (online)	1095-9130
ISSN	1046-2023
DOI	10.1016/j.ymeth.2021.06.009
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Article ; Online: The effect of Mg2+ on Ca2+ binding to cardiac troponin C in hypertrophic cardiomyopathy associated TNNC1 variants

Rayani, Kaveh / Hantz, Eric R. / Haji‐Ghassemi, Omid / Li, Alison Y. / Spuches, Anne M. / Van Petegem, Filip / Solaro, R. John / Lindert, Steffen / Tibbits, Glen F.

The FEBS Journal. 2022 Dec., v. 289, no. 23 p.7446-7465

2022

Abstract: Cardiac troponin C (cTnC) is the critical Ca²⁺‐sensing component of the troponin complex. Binding of Ca²⁺ to cTnC triggers a cascade of conformational changes within the myofilament that culminate in force production. Hypertrophic cardiomyopathy (HCM)‐ ... ...

Abstract	Cardiac troponin C (cTnC) is the critical Ca²⁺‐sensing component of the troponin complex. Binding of Ca²⁺ to cTnC triggers a cascade of conformational changes within the myofilament that culminate in force production. Hypertrophic cardiomyopathy (HCM)‐associated TNNC1 variants generally induce a greater degree and duration of Ca²⁺ binding, which may underly the hypertrophic phenotype. Regulation of contraction has long been thought to occur exclusively through Ca²⁺ binding to site II of cTnC. However, work by several groups including ours suggest that Mg²⁺, which is several orders of magnitude more abundant in the cell than Ca²⁺, may compete for binding to the same cTnC regulatory site. We previously used isothermal titration calorimetry (ITC) to demonstrate that physiological concentrations of Mg²⁺ may decrease site II Ca²⁺‐binding in both N‐terminal and full‐length cTnC. Here, we explore the binding of Ca²⁺ and Mg²⁺ to cTnC harbouring a series of TNNC1 variants thought to be causal in HCM. ITC and thermodynamic integration (TI) simulations show that A8V, L29Q and A31S elevate the affinity for both Ca²⁺ and Mg²⁺. Further, L48Q, Q50R and C84Y that are adjacent to the EF hand binding motif of site II have a more significant effect on affinity and the thermodynamics of the binding interaction. To the best of our knowledge, this work is the first to explore the role of Mg²⁺ in modifying the Ca²⁺ affinity of cTnC mutations linked to HCM. Our results indicate a physiologically significant role for cellular Mg²⁺ both at baseline and when elevated on modifying the Ca²⁺ binding properties of cTnC and the subsequent conformational changes which precede cardiac contraction.
Keywords	calcium ; calorimetry ; cardiomyopathy ; phenotype ; thermodynamics ; titration ; troponin C
Language	English
Dates of publication	2022-12
Size	p. 7446-7465.
Publishing place	John Wiley & Sons, Ltd
Document type	Article ; Online
Note	JOURNAL ARTICLE
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/febs.16578
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Article ; Online: Advances in Hypertrophic Cardiomyopathy Disease Modelling Using hiPSC-Derived Cardiomyocytes.

Dababneh, Saif / Hamledari, Homa / Maaref, Yasaman / Jayousi, Farah / Hosseini, Dina B / Khan, Aasim / Jannati, Shayan / Jabbari, Kosar / Arslanova, Alia / Butt, Mariam / Roston, Thomas M / Sanatani, Shubhayan / Tibbits, Glen F

The Canadian journal of cardiology

2023

Abstract: The advent of human induced pluripotent stem cells (hiPSCs) and their capacity to be differentiated into beating human cardiomyocytes (CMs) in vitro has revolutionized human disease modelling, genotype-phenotype predictions, and therapeutic testing. ... ...

Abstract	The advent of human induced pluripotent stem cells (hiPSCs) and their capacity to be differentiated into beating human cardiomyocytes (CMs) in vitro has revolutionized human disease modelling, genotype-phenotype predictions, and therapeutic testing. Hypertrophic cardiomyopathy (HCM) is a common inherited cardiomyopathy and the leading known cause of sudden cardiac arrest in young adults and athletes. On a molecular level, HCM is often driven by single pathogenic genetic variants, usually in sarcomeric proteins, that can alter the mechanical, electrical, signalling, and transcriptional properties of the cell. A deeper knowledge of these alterations is critical to better understanding HCM manifestation, progression, and treatment. Leveraging hiPSC-CMs to investigate the molecular mechanisms driving HCM presents a unique opportunity to dissect the consequences of genetic variants in a sophisticated and controlled manner. In this review, we summarize the molecular underpinnings of HCM and the role of hiPSC-CM studies in advancing our understanding, and we highlight the advances in hiPSC-CM-based modelling of HCM, including maturation, contractility, multiomics, and genome editing, with the notable exception of electrophysiology, which has been previously covered.
Language	English
Publishing date	2023-11-10
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	632813-1
ISSN	1916-7075 ; 0828-282X
ISSN (online)	1916-7075
ISSN	0828-282X
DOI	10.1016/j.cjca.2023.11.009
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Article ; Online: Pediatric Catecholaminergic Polymorphic Ventricular Tachycardia: A Translational Perspective for the Clinician-Scientist.

Kallas, Dania / Lamba, Avani / Roston, Thomas M / Arslanova, Alia / Franciosi, Sonia / Tibbits, Glen F / Sanatani, Shubhayan

International journal of molecular sciences

2021 Volume 22, Issue 17

Abstract: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare and potentially lethal inherited arrhythmia disease characterized by exercise or emotion-induced bidirectional or polymorphic ventricular tachyarrhythmias. The median age of disease ... ...

Abstract	Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare and potentially lethal inherited arrhythmia disease characterized by exercise or emotion-induced bidirectional or polymorphic ventricular tachyarrhythmias. The median age of disease onset is reported to be approximately 10 years of age. The majority of CPVT patients have pathogenic variants in the gene encoding the cardiac ryanodine receptor, or calsequestrin 2. These lead to mishandling of calcium in cardiomyocytes resulting in after-depolarizations, and ventricular arrhythmias. Disease severity is particularly pronounced in younger individuals who usually present with cardiac arrest and arrhythmic syncope. Risk stratification is imprecise and long-term prognosis on therapy is unknown despite decades of research focused on pediatric CPVT populations. The purpose of this review is to summarize contemporary data on pediatric CPVT, highlight knowledge gaps and present future research directions for the clinician-scientist to address.
MeSH term(s)	Child ; Emotions/physiology ; Exercise ; Humans ; Mutation ; Ryanodine Receptor Calcium Release Channel/genetics ; Tachycardia, Ventricular/genetics ; Tachycardia, Ventricular/pathology ; Tachycardia, Ventricular/therapy
Chemical Substances	Ryanodine Receptor Calcium Release Channel
Language	English
Publishing date	2021-08-27
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22179293
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