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Article ; Online: Next-generation sequencing strategies in venous thromboembolism: in whom and for what purpose?

Trégouët, David-Alexandre / Morange, Pierre-Emmanuel

Journal of thrombosis and haemostasis : JTH

2024

Abstract: This invited review follows the oral presentation "To Sequence or Not to Sequence, That Is Not the Question; But 'When, Who, Which and What For?' Is" given during the State of the Art session "Translational Genomics in Thrombosis: From OMICs to Clinics" ... ...

Abstract	This invited review follows the oral presentation "To Sequence or Not to Sequence, That Is Not the Question; But 'When, Who, Which and What For?' Is" given during the State of the Art session "Translational Genomics in Thrombosis: From OMICs to Clinics" of the International Society on Thrombosis and Haemostasis 2023 Congress. Emphasizing the power of next-generation sequencing technologies and the diverse strategies associated with DNA variant analysis, this review highlights the unresolved questions and challenges in their implementation both for the clinical diagnosis of venous thromboembolism and in translational research.
Language	English
Publishing date	2024-04-18
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2112661-6
ISSN	1538-7836 ; 1538-7933
ISSN (online)	1538-7836
ISSN	1538-7933
DOI	10.1016/j.jtha.2024.04.004
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Article ; Online: Post-transcriptional control of haemostatic genes: mechanisms and emerging therapeutic concepts in thrombo-inflammatory disorders.

Danckwardt, Sven / Trégouët, David-Alexandre / Castoldi, Elisabetta

Cardiovascular research

2023 Volume 119, Issue 8, Page(s) 1624–1640

Abstract: The haemostatic system is pivotal to maintaining vascular integrity. Multiple components involved in blood coagulation have central functions in inflammation and immunity. A derailed haemostasis is common in prevalent pathologies such as sepsis, ... ...

Abstract	The haemostatic system is pivotal to maintaining vascular integrity. Multiple components involved in blood coagulation have central functions in inflammation and immunity. A derailed haemostasis is common in prevalent pathologies such as sepsis, cardiovascular disorders, and lately, COVID-19. Physiological mechanisms limit the deleterious consequences of a hyperactivated haemostatic system through adaptive changes in gene expression. While this is mainly regulated at the level of transcription, co- and posttranscriptional mechanisms are increasingly perceived as central hubs governing multiple facets of the haemostatic system. This layer of regulation modulates the biogenesis of haemostatic components, for example in situations of increased turnover and demand. However, they can also be 'hijacked' in disease processes, thereby perpetuating and even causally entertaining associated pathologies. This review summarizes examples and emerging concepts that illustrate the importance of posttranscriptional mechanisms in haemostatic control and crosstalk with the immune system. It also discusses how such regulatory principles can be used to usher in new therapeutic concepts to combat global medical threats such as sepsis or cardiovascular disorders.
MeSH term(s)	Humans ; Hemostatics ; COVID-19/genetics ; Hemostasis/genetics ; Gene Expression Regulation ; Blood Coagulation/genetics ; Cardiovascular Diseases/genetics ; Cardiovascular Diseases/therapy ; MicroRNAs/genetics
Chemical Substances	Hemostatics ; MicroRNAs
Language	English
Publishing date	2023-03-24
Publishing country	England
Document type	Review ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80340-6
ISSN	1755-3245 ; 0008-6363
ISSN (online)	1755-3245
ISSN	0008-6363
DOI	10.1093/cvr/cvad046
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Article: Small Open Reading Frames, How to Find Them and Determine Their Function.

Kute, Preeti Madhav / Soukarieh, Omar / Tjeldnes, Håkon / Trégouët, David-Alexandre / Valen, Eivind

Frontiers in genetics

2022 Volume 12, Page(s) 796060

Abstract: Advances in genomics and molecular biology have revealed an abundance of small open reading frames (sORFs) across all types of transcripts. While these sORFs are often assumed to be non-functional, many have been implicated in physiological functions and ...

Abstract	Advances in genomics and molecular biology have revealed an abundance of small open reading frames (sORFs) across all types of transcripts. While these sORFs are often assumed to be non-functional, many have been implicated in physiological functions and a significant number of sORFs have been described in human diseases. Thus, sORFs may represent a hidden repository of functional elements that could serve as therapeutic targets. Unlike protein-coding genes, it is not necessarily the encoded peptide of an sORF that enacts its function, sometimes simply the act of translating an sORF might have a regulatory role. Indeed, the most studied sORFs are located in the 5'UTRs of coding transcripts and can have a regulatory impact on the translation of the downstream protein-coding sequence. However, sORFs have also been abundantly identified in non-coding RNAs including lncRNAs, circular RNAs and ribosomal RNAs suggesting that sORFs may be diverse in function. Of the many different experimental methods used to discover sORFs, the most commonly used are ribosome profiling and mass spectrometry. These can confirm interactions between transcripts and ribosomes and the production of a peptide, respectively. Extensions to ribosome profiling, which also capture scanning ribosomes, have further made it possible to see how sORFs impact the translation initiation of mRNAs. While high-throughput techniques have made the identification of sORFs less difficult, defining their function, if any, is typically more challenging. Together, the abundance and potential function of many of these sORFs argues for the necessity of including sORFs in gene annotations and systematically characterizing these to understand their potential functional roles. In this review, we will focus on the high-throughput methods used in the detection and characterization of sORFs and discuss techniques for validation and functional characterization.
Language	English
Publishing date	2022-01-28
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2606823-0
ISSN	1664-8021
ISSN	1664-8021
DOI	10.3389/fgene.2021.796060
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Article ; Online: uAUG creating variants in the 5'UTR of ENG causing Hereditary Hemorrhagic Telangiectasia.

Soukarieh, Omar / Tillet, Emmanuelle / Proust, Carole / Dupont, Charlène / Jaspard-Vinassa, Béatrice / Soubrier, Florent / Goyenvalle, Aurélie / Eyries, Mélanie / Trégouët, David-Alexandre

NPJ genomic medicine

2023 Volume 8, Issue 1, Page(s) 32

Abstract: Hereditary Hemorrhagic Telangiectasia (HHT) is a rare, autosomal dominant, vascular disorder. About 80% of cases are caused by pathogenic variants in ACVRL1 (also known as ALK1) and ENG, with the remaining cases being unexplained. We identified two ... ...

Abstract	Hereditary Hemorrhagic Telangiectasia (HHT) is a rare, autosomal dominant, vascular disorder. About 80% of cases are caused by pathogenic variants in ACVRL1 (also known as ALK1) and ENG, with the remaining cases being unexplained. We identified two variants, c.-79C>T and c.-68G>A, in the 5'UTR of ENG in two unrelated patients. They create upstream AUGs at the origin of upstream overlapping open reading frames (uoORFs) ending at the same stop codon. To assess the pathogenicity of these variants, we performed functional assays based on the expression of wild-type and mutant constructs in human cells and evaluated their effect on ALK1 activity in a BMP-response element assay. This assay is mandatory for molecular diagnosis and has been so far only applied to coding ENG variants. These variants were associated with a decrease of protein levels in HeLa and HUVEC cells and a decreased ability to activate ALK1. We applied the same experiments on three additional uoORF-creating variants (c.-142A>T, c.-127C>T and c.-10C>T) located in the 5'UTR of ENG and previously reported in HHT patients. We found that all the analyzed variants alter protein levels and function. Additional experiments relying on an artificial deletion in our mutated constructs show that identified uAUGs could initiate the translation indicating that the associated effect is translation-dependent. Overall, we have identified two 5'UTR ENG variations in HHT patients and shed new light on the role of upstream ORFs on ENG regulation. Our findings contribute to the amelioration of molecular diagnosis in HHT.
Language	English
Publishing date	2023-10-17
Publishing country	England
Document type	Journal Article
ZDB-ID	2813848-X
ISSN	2056-7944 ; 2056-7944
ISSN (online)	2056-7944
ISSN	2056-7944
DOI	10.1038/s41525-023-00378-5
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Article ; Online: Addressing unmeasured confounders in cohort studies: Instrumental variable method for a time-fixed exposure on an outcome trajectory.

Le Bourdonnec, Kateline / Samieri, Cécilia / Tzourio, Christophe / Mura, Thibault / Mishra, Aniket / Trégouët, David-Alexandre / Proust-Lima, Cécile

Biometrical journal. Biometrische Zeitschrift

2023 Volume 66, Issue 1, Page(s) e2200358

Abstract: Instrumental variable methods, which handle unmeasured confounding by targeting the part of the exposure explained by an exogenous variable not subject to confounding, have gained much interest in observational studies. We consider the very frequent ... ...

Abstract	Instrumental variable methods, which handle unmeasured confounding by targeting the part of the exposure explained by an exogenous variable not subject to confounding, have gained much interest in observational studies. We consider the very frequent setting of estimating the unconfounded effect of an exposure measured at baseline on the subsequent trajectory of an outcome repeatedly measured over time. We didactically explain how to apply the instrumental variable method in such setting by adapting the two-stage classical methodology with (1) the prediction of the exposure according to the instrumental variable, (2) its inclusion into a mixed model to quantify the exposure association with the subsequent outcome trajectory, and (3) the computation of the estimated total variance. A simulation study illustrates the consequences of unmeasured confounding in classical analyses and the usefulness of the instrumental variable approach. The methodology is then applied to 6224 participants of the 3C cohort to estimate the association of type-2 diabetes with subsequent cognitive trajectory, using 42 genetic polymorphisms as instrumental variables. This contribution shows how to handle endogeneity when interested in repeated outcomes, along with a R implementation. However, it should still be used with caution as it relies on instrumental variable assumptions hardly testable in practice.
MeSH term(s)	Humans ; Confounding Factors, Epidemiologic ; Cohort Studies ; Computer Simulation ; Bias
Language	English
Publishing date	2023-12-14
Publishing country	Germany
Document type	Journal Article
ZDB-ID	131640-0
ISSN	1521-4036 ; 0323-3847 ; 0006-3452
ISSN (online)	1521-4036
ISSN	0323-3847 ; 0006-3452
DOI	10.1002/bimj.202200358
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Article ; Online: What is currently known about the genetics of venous thromboembolism at the dawn of next generation sequencing technologies.

Trégouët, David-Alexandre / Morange, Pierre-Emmanuel

British journal of haematology

2017

Abstract: Venous thromboembolism (VTE) has a strong genetic component. This review summarizes what is known at the seventeen genes that are now well established to harbour VTE-associated genetic variants. In addition, it discusses additional candidate genes that ... ...

Abstract	Venous thromboembolism (VTE) has a strong genetic component. This review summarizes what is known at the seventeen genes that are now well established to harbour VTE-associated genetic variants. In addition, it discusses additional candidate genes that deserve further validation before being claimed as VTE associated genes. Finally, several research strategies are briefly described to identify other molecular determinants of the disease.
Language	English
Publishing date	2017-10-29
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	80077-6
ISSN	1365-2141 ; 0007-1048
ISSN (online)	1365-2141
ISSN	0007-1048
DOI	10.1111/bjh.15004
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Article ; Online: Impaired balance between neutrophil extracellular trap formation and degradation by DNases in COVID-19 disease.

Garcia, Geoffrey / Labrouche-Colomer, Sylvie / Duvignaud, Alexandre / Clequin, Etienne / Dussiau, Charles / Trégouët, David-Alexandre / Malvy, Denis / Prevel, Renaud / Zouine, Atika / Pellegrin, Isabelle / Goret, Julien / Mamani-Matsuda, Maria / Dewitte, Antoine / James, Chloe

Journal of translational medicine

2024 Volume 22, Issue 1, Page(s) 246

Abstract: Background: Thrombo-inflammation and neutrophil extracellular traps (NETs) are exacerbated in severe cases of COVID-19, potentially contributing to disease exacerbation. However, the mechanisms underpinning this dysregulation remain elusive. We ... ...

Abstract	Background: Thrombo-inflammation and neutrophil extracellular traps (NETs) are exacerbated in severe cases of COVID-19, potentially contributing to disease exacerbation. However, the mechanisms underpinning this dysregulation remain elusive. We hypothesised that lower DNase activity may be associated with higher NETosis and clinical worsening in patients with COVID-19. Methods: Biological samples were obtained from hospitalized patients (15 severe, 37 critical at sampling) and 93 non-severe ambulatory cases. Our aims were to compare NET biomarkers, functional DNase levels, and explore mechanisms driving any imbalance concerning disease severity. Results: Functional DNase levels were diminished in the most severe patients, paralleling an imbalance between NET markers and DNase activity. DNase1 antigen levels were higher in ambulatory cases but lower in severe patients. DNase1L3 antigen levels remained consistent across subgroups, not rising alongside NET markers. DNASE1 polymorphisms correlated with reduced DNase1 antigen levels. Moreover, a quantitative deficiency in plasmacytoid dendritic cells (pDCs), which primarily express DNase1L3, was observed in critical patients. Analysis of public single-cell RNAseq data revealed reduced DNase1L3 expression in pDCs from severe COVID-19 patient. Conclusion: Severe and critical COVID-19 cases exhibited an imbalance between NET and DNase functional activity and quantity. Early identification of NETosis imbalance could guide targeted therapies against thrombo-inflammation in COVID-19-related sepsis, such as DNase administration, to avert clinical deterioration. Trial registration: COVERAGE trial (NCT04356495) and COLCOV19-BX study (NCT04332016).
MeSH term(s)	Humans ; Extracellular Traps/metabolism ; Neutrophils/metabolism ; Deoxyribonucleases/metabolism ; COVID-19 ; Deoxyribonuclease I/metabolism ; Inflammation/metabolism ; Nervous System Diseases
Chemical Substances	Deoxyribonucleases (EC 3.1.-) ; Deoxyribonuclease I (EC 3.1.21.1)
Language	English
Publishing date	2024-03-07
Publishing country	England
Document type	Journal Article
ZDB-ID	2118570-0
ISSN	1479-5876 ; 1479-5876
ISSN (online)	1479-5876
ISSN	1479-5876
DOI	10.1186/s12967-024-05044-7
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Article ; Online: CAVIN1-Mediated hERG Dynamics: A Novel Mechanism Underlying the Interindividual Variability in Drug-Induced Long QT.

Al Sayed, Zeina R / Pereira, Céline / Le Borgne, Rémi / Viaris de Lesegno, Christine / Jouve, Charlène / Pénard, Esthel / Mallet, Adeline / Masurkar, Nihar / Loussouarn, Gildas / Verbavatz, Jean-Marc / Lamaze, Christophe / Trégouët, David-Alexandre / Hulot, Jean-Sébastien

Circulation

2024

Abstract: Background: Drug-induced QT prolongation (diLQT) is a feared side effect that could expose susceptible individuals to fatal arrhythmias. The occurrence of diLQT is primarily attributed to unintended drug interactions with cardiac ion channels, notably ... ...

Abstract	Background: Drug-induced QT prolongation (diLQT) is a feared side effect that could expose susceptible individuals to fatal arrhythmias. The occurrence of diLQT is primarily attributed to unintended drug interactions with cardiac ion channels, notably the hERG (human ether-a-go-go-related gene) channels that generate the delayed-rectifier potassium current (I Methods: We measured electrophysiological activity and cellular distribution of hERG channels after hERG blocker treatment in iPS-CMs derived from patients with highest sensitivity (HS) or lowest sensitivity (LS) to sotalol administration in vivo (ie, on the basis of the measure of the maximal change in QT interval 3 hours after administration). Specific small interfering RNAs and CAVIN1-T2A-GFP adenovirus were used to manipulate Results: Whereas HS and LS iPS-CMs showed similar electrophysiological characteristics at baseline, the late repolarization phase was prolonged and I Conclusions: Our study identifies unbridled turnover of the potassium channel hERG as a mechanism supporting the interindividual susceptibility underlying diLQT development and demonstrates how this phenomenon is finely tuned by CAVIN1.
Language	English
Publishing date	2024-04-29
Publishing country	United States
Document type	Journal Article
ZDB-ID	80099-5
ISSN	1524-4539 ; 0009-7322 ; 0069-4193 ; 0065-8499
ISSN (online)	1524-4539
ISSN	0009-7322 ; 0069-4193 ; 0065-8499
DOI	10.1161/CIRCULATIONAHA.123.063917
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Article: Common and Rare 5'UTR Variants Altering Upstream Open Reading Frames in Cardiovascular Genomics.

Soukarieh, Omar / Meguerditchian, Caroline / Proust, Carole / Aïssi, Dylan / Eyries, Mélanie / Goyenvalle, Aurélie / Trégouët, David-Alexandre

Frontiers in cardiovascular medicine

2022 Volume 9, Page(s) 841032

Abstract: High-throughput sequencing (HTS) technologies are revolutionizing the research and molecular diagnosis landscape by allowing the exploration of millions of nucleotide sequences at an unprecedented scale. These technologies are of particular interest in ... ...

Abstract	High-throughput sequencing (HTS) technologies are revolutionizing the research and molecular diagnosis landscape by allowing the exploration of millions of nucleotide sequences at an unprecedented scale. These technologies are of particular interest in the identification of genetic variations contributing to the risk of rare (Mendelian) and common (multifactorial) human diseases. So far, they have led to numerous successes in identifying rare disease-causing mutations in coding regions, but few in non-coding regions that include introns, untranslated (UTR), and intergenic regions. One class of neglected non-coding variations is that of 5'UTR variants that alter upstream open reading frames (upORFs) of the coding sequence (CDS) of a natural protein coding transcript. Following a brief summary of the molecular bases of the origin and functions of upORFs, we will first review known 5'UTR variations altering upORFs and causing rare cardiovascular disorders (CVDs). We will then investigate whether upORF-affecting single nucleotide polymorphisms could be good candidates for explaining association signals detected in the context of genome-wide association studies for common complex CVDs.
Language	English
Publishing date	2022-03-21
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2781496-8
ISSN	2297-055X
ISSN	2297-055X
DOI	10.3389/fcvm.2022.841032
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Article ; Online: Association of ABO blood groups with venous thrombosis recurrence in middle-aged patients: insights from a weighted Cox analysis dedicated to ambispective design.

Munsch, Gaëlle / Goumidi, Louisa / van Hylckama Vlieg, Astrid / Ibrahim-Kosta, Manal / Bruzelius, Maria / Deleuze, Jean-François / Rosendaal, Frits R / Jacqmin-Gadda, Hélène / Morange, Pierre-Emmanuel / Trégouët, David-Alexandre

BMC medical research methodology

2023 Volume 23, Issue 1, Page(s) 99

Abstract: Background: In studies of time-to-events, it is common to collect information about events that occurred before the inclusion in a prospective cohort. When the studied risk factors are independent of time, including both pre- and post-inclusion events ... ...

Abstract	Background: In studies of time-to-events, it is common to collect information about events that occurred before the inclusion in a prospective cohort. When the studied risk factors are independent of time, including both pre- and post-inclusion events in the analyses, generally referred to as relying on an ambispective design, increases the statistical power but may lead to a selection bias. In the field of venous thromboembolism (VT), ABO blood groups have been the subject of extensive research due to their substantial effect on VT risk. However, few studies have investigated their effect on the risk of VT recurrence. Motivated by the study of the association of genetically determined ABO blood groups with VT recurrence, we propose a methodology to include pre-inclusion events in the analysis of ambispective studies while avoiding the selection bias due to mortality. Methods: This work relies on two independent cohorts of VT patients, the French MARTHA study built on an ambispective design and the Dutch MEGA study built on a standard prospective design. For the analysis of the MARTHA study, a weighted Cox model was developed where weights were defined by the inverse of the survival probability at the time of data collection about the events. Thanks to the collection of information on the vital status of patients, we could estimate the survival probabilities using a delayed-entry Cox model on the death risk. Finally, results obtained in both studies were then meta-analysed. Results: In the combined sample totalling 2,752 patients including 993 recurrences, the A1 blood group has an increased risk (Hazard Ratio (HR) of 1.18, p = 4.2 × 10 Conclusion: The proposed methodology increases the power of studies relying on an ambispective design which is frequent in epidemiologic studies about recurrent events. This approach allowed to clarify the association of ABO blood groups with the risk of VT recurrence. Besides, this methodology has an immediate field of application in the context of genome wide association studies.
MeSH term(s)	Middle Aged ; Humans ; ABO Blood-Group System/genetics ; Genome-Wide Association Study ; Venous Thrombosis/genetics ; Venous Thrombosis/complications ; Risk Factors ; Proportional Hazards Models ; Recurrence
Chemical Substances	ABO Blood-Group System
Language	English
Publishing date	2023-04-22
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2041362-2
ISSN	1471-2288 ; 1471-2288
ISSN (online)	1471-2288
ISSN	1471-2288
DOI	10.1186/s12874-023-01915-7
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