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Article ; Online: Updates on diagnostic criteria for hereditary haemorrhagic telangiectasia in the light of whole genome sequencing of 'gene-negative' individuals recruited to the 100 000 Genomes Project.

Shovlin, Claire L / Almaghlouth, Fatma I / Alsafi, Ali / Coote, Nicola / Rennie, Catherine / Wallace, Gillian Mf / Govani, Fatima S / Research Consortium, Genomics England

Journal of medical genetics

2024 Volume 61, Issue 2, Page(s) 182–185

MeSH term(s)	Humans ; Telangiectasia, Hereditary Hemorrhagic/diagnosis ; Telangiectasia, Hereditary Hemorrhagic/genetics ; Mutation ; Phenotype ; Whole Genome Sequencing
Language	English
Publishing date	2024-01-19
Publishing country	England
Document type	Journal Article
ZDB-ID	220881-7
ISSN	1468-6244 ; 0022-2593
ISSN (online)	1468-6244
ISSN	0022-2593
DOI	10.1136/jmg-2023-109195
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Article ; Online: Fine mapping of the hereditary haemorrhagic telangiectasia (HHT)3 locus on chromosome 5 excludes VE-Cadherin-2, Sprouty4 and other interval genes.

Govani, Fatima S / Shovlin, Claire L

Journal of angiogenesis research

2010 Volume 2, Page(s) 15

Abstract: Background: There is significant interest in new loci for the inherited condition hereditary haemorrhagic telangiectasia (HHT) because the known disease genes encode proteins involved in vascular transforming growth factor (TGF)-beta signalling pathways, ...

Abstract	Background: There is significant interest in new loci for the inherited condition hereditary haemorrhagic telangiectasia (HHT) because the known disease genes encode proteins involved in vascular transforming growth factor (TGF)-beta signalling pathways, and the disease phenotype appears to be unmasked or provoked by angiogenesis in man and animal models. In a previous study, we mapped a new locus for HHT (HHT3) to a 5.7 Mb region of chromosome 5. Some of the polymorphic markers used had been uninformative in key recombinant individuals, leaving two potentially excludable regions, one of which contained loci for attractive candidate genes encoding VE Cadherin-2, Sprouty4 and FGF1, proteins involved in angiogenesis. Methods: Extended analyses in the interval-defining pedigree were performed using informative genomic sequence variants identified during candidate gene sequencing. These variants were amplified by polymerase chain reaction; sequenced on an ABI 3730xl, and analysed using FinchTV V1.4.0 software. Results: Informative genomic sequence variants were used to construct haplotypes permitting more precise citing of recombination breakpoints. These reduced the uninformative centromeric region from 141.2-144 Mb to between 141.9-142.6 Mb, and the uninformative telomeric region from 145.2-146.9 Mb to between 146.1-146.4 Mb. Conclusions: The HHT3 interval on chromosome 5 was reduced to 4.5 Mb excluding 30% of the coding genes in the original HHT3 interval. Strong candidates VE-cadherin-2 and Sprouty4 cannot be HHT3.
Language	English
Publishing date	2010-08-11
Publishing country	England
Document type	Journal Article
ZDB-ID	2516062-X
ISSN	2040-2384 ; 2040-2384
ISSN (online)	2040-2384
ISSN	2040-2384
DOI	10.1186/2040-2384-2-15
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Article ; Online: Hereditary haemorrhagic telangiectasia: a clinical and scientific review.

Govani, Fatima S / Shovlin, Claire L

European journal of human genetics : EJHG

2009 Volume 17, Issue 7, Page(s) 860–871

Abstract: The autosomal-dominant trait hereditary haemorrhagic telangiectasia (HHT) affects 1 in 5-8000 people. Genes mutated in HHT (most commonly for endoglin or activin receptor-like kinase (ALK1)) encode proteins that modulate transforming growth factor (TGF)- ... ...

Abstract	The autosomal-dominant trait hereditary haemorrhagic telangiectasia (HHT) affects 1 in 5-8000 people. Genes mutated in HHT (most commonly for endoglin or activin receptor-like kinase (ALK1)) encode proteins that modulate transforming growth factor (TGF)-beta superfamily signalling in vascular endothelial cells; mutations lead to the development of fragile telangiectatic vessels and arteriovenous malformations. In this article, we review the underlying molecular, cellular and circulatory pathobiology; explore HHT clinical and genetic diagnostic strategies; present detailed considerations regarding screening for asymptomatic visceral involvement; and provide overviews of management strategies.
MeSH term(s)	Activin Receptors, Type II/genetics ; Antigens, CD/genetics ; Endoglin ; Hemorrhage ; Humans ; Mutation ; Receptors, Cell Surface/genetics ; Signal Transduction ; Telangiectasia, Hereditary Hemorrhagic/genetics ; Telangiectasia, Hereditary Hemorrhagic/metabolism ; Telangiectasia, Hereditary Hemorrhagic/physiopathology ; Transforming Growth Factor beta/metabolism
Chemical Substances	Antigens, CD ; ENG protein, human ; Endoglin ; Receptors, Cell Surface ; Transforming Growth Factor beta ; ACVRL1 protein, human (EC 2.7.11.30) ; Activin Receptors, Type II (EC 2.7.11.30)
Language	English
Publishing date	2009-04-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1141470-4
ISSN	1476-5438 ; 1018-4813
ISSN (online)	1476-5438
ISSN	1018-4813
DOI	10.1038/ejhg.2009.35
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Article ; Online: Fine mapping of the hereditary haemorrhagic telangiectasia (HHT)3 locus on chromosome 5 excludes VE-Cadherin-2, Sprouty4 and other interval genes

Govani Fatima S / Shovlin Claire L

Journal of Angiogenesis Research, Vol 2, Iss 1, p

2010 Volume 15

Abstract: Abstract Background There is significant interest in new loci for the inherited condition hereditary haemorrhagic telangiectasia (HHT) because the known disease genes encode proteins involved in vascular transforming growth factor (TGF)-β signalling ... ...

Abstract	Abstract Background There is significant interest in new loci for the inherited condition hereditary haemorrhagic telangiectasia (HHT) because the known disease genes encode proteins involved in vascular transforming growth factor (TGF)-β signalling pathways, and the disease phenotype appears to be unmasked or provoked by angiogenesis in man and animal models. In a previous study, we mapped a new locus for HHT ( HHT3 ) to a 5.7 Mb region of chromosome 5. Some of the polymorphic markers used had been uninformative in key recombinant individuals, leaving two potentially excludable regions, one of which contained loci for attractive candidate genes encoding VE Cadherin-2, Sprouty4 and FGF1, proteins involved in angiogenesis. Methods Extended analyses in the interval-defining pedigree were performed using informative genomic sequence variants identified during candidate gene sequencing. These variants were amplified by polymerase chain reaction; sequenced on an ABI 3730xl, and analysed using FinchTV V1.4.0 software. Results Informative genomic sequence variants were used to construct haplotypes permitting more precise citing of recombination breakpoints. These reduced the uninformative centromeric region from 141.2-144 Mb to between 141.9-142.6 Mb, and the uninformative telomeric region from 145.2-146.9 Mb to between 146.1-146.4 Mb. Conclusions The HHT3 interval on chromosome 5 was reduced to 4.5 Mb excluding 30% of the coding genes in the original HHT3 interval. Strong candidates VE-cadherin-2 and Sprouty4 cannot be HHT3 .
Keywords	Diseases of the circulatory (Cardiovascular) system ; RC666-701 ; Specialties of internal medicine ; RC581-951 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Cardiovascular ; DOAJ:Medicine (General) ; DOAJ:Health Sciences ; Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282 ; DOAJ:Oncology
Subject code	572
Language	English
Publishing date	2010-08-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Low Dose Iron Treatments Induce a DNA Damage Response in Human Endothelial Cells within Minutes.

Mollet, Inês G / Patel, Dilipkumar / Govani, Fatima S / Giess, Adam / Paschalaki, Koralia / Periyasamy, Manikandan / Lidington, Elaine C / Mason, Justin C / Jones, Michael D / Game, Laurence / Ali, Simak / Shovlin, Claire L

PloS one

2016 Volume 11, Issue 2, Page(s) e0147990

Abstract: Background: Spontaneous reports from patients able to report vascular sequelae in real time, and recognition that serum non transferrin bound iron may reach or exceed 10μmol/L in the blood stream after iron tablets or infusions, led us to hypothesize ... ...

Abstract	Background: Spontaneous reports from patients able to report vascular sequelae in real time, and recognition that serum non transferrin bound iron may reach or exceed 10μmol/L in the blood stream after iron tablets or infusions, led us to hypothesize that conventional iron treatments may provoke acute vascular injury. This prompted us to examine whether a phenotype could be observed in normal human endothelial cells treated with low dose iron. Methodology: Confluent primary human endothelial cells (EC) were treated with filter-sterilized iron (II) citrate or fresh media for RNA sequencing and validation studies. RNA transcript profiles were evaluated using directional RNA sequencing with no pre-specification of target sequences. Alignments were counted for exons and junctions of the gene strand only, blinded to treatment types. Principal findings: Rapid changes in RNA transcript profiles were observed in endothelial cells treated with 10μmol/L iron (II) citrate, compared to media-treated cells. Clustering for Gene Ontology (GO) performed on all differentially expressed genes revealed significant differences in biological process terms between iron and media-treated EC, whereas 10 sets of an equivalent number of randomly selected genes from the respective EC gene datasets showed no significant differences in any GO terms. After 1 hour, differentially expressed genes clustered to vesicle mediated transport, protein catabolism, and cell cycle (Benjamini p = 0.0016, 0.0024 and 0.0032 respectively), and by 6 hours, to cellular response to DNA damage stimulus most significantly through DNA repair genes FANCG, BLM, and H2AFX. Comet assays demonstrated that 10μM iron treatment elicited DNA damage within 1 hour. This was accompanied by a brisk DNA damage response pulse, as ascertained by the development of DNA damage response (DDR) foci, and p53 stabilization. Significance: These data suggest that low dose iron treatments are sufficient to modify the vascular endothelium, and induce a DNA damage response.
MeSH term(s)	Cell Cycle ; Citrates/administration & dosage ; Cluster Analysis ; Comet Assay ; DNA Damage/drug effects ; Dose-Response Relationship, Drug ; Endothelial Cells/cytology ; Endothelial Cells/drug effects ; Exons ; Gene Expression Profiling ; Gene Expression Regulation ; Histones/metabolism ; Human Umbilical Vein Endothelial Cells ; Humans ; Iron/administration & dosage ; Microcirculation ; Phenotype ; Phosphorylation ; Sequence Analysis, RNA ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	Citrates ; H2AX protein, human ; Histones ; TP53 protein, human ; Tumor Suppressor Protein p53 ; Iron (E1UOL152H7)
Language	English
Publishing date	2016-02-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0147990
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Article ; Online: Low Dose Iron Treatments Induce a DNA Damage Response in Human Endothelial Cells within Minutes.

Inês G Mollet / Dilipkumar Patel / Fatima S Govani / Adam Giess / Koralia Paschalaki / Manikandan Periyasamy / Elaine C Lidington / Justin C Mason / Michael D Jones / Laurence Game / Simak Ali / Claire L Shovlin

PLoS ONE, Vol 11, Iss 2, p e

2016 Volume 0147990

Abstract: Spontaneous reports from patients able to report vascular sequelae in real time, and recognition that serum non transferrin bound iron may reach or exceed 10μmol/L in the blood stream after iron tablets or infusions, led us to hypothesize that ... ...

Abstract	Spontaneous reports from patients able to report vascular sequelae in real time, and recognition that serum non transferrin bound iron may reach or exceed 10μmol/L in the blood stream after iron tablets or infusions, led us to hypothesize that conventional iron treatments may provoke acute vascular injury. This prompted us to examine whether a phenotype could be observed in normal human endothelial cells treated with low dose iron.Confluent primary human endothelial cells (EC) were treated with filter-sterilized iron (II) citrate or fresh media for RNA sequencing and validation studies. RNA transcript profiles were evaluated using directional RNA sequencing with no pre-specification of target sequences. Alignments were counted for exons and junctions of the gene strand only, blinded to treatment types.Rapid changes in RNA transcript profiles were observed in endothelial cells treated with 10μmol/L iron (II) citrate, compared to media-treated cells. Clustering for Gene Ontology (GO) performed on all differentially expressed genes revealed significant differences in biological process terms between iron and media-treated EC, whereas 10 sets of an equivalent number of randomly selected genes from the respective EC gene datasets showed no significant differences in any GO terms. After 1 hour, differentially expressed genes clustered to vesicle mediated transport, protein catabolism, and cell cycle (Benjamini p = 0.0016, 0.0024 and 0.0032 respectively), and by 6 hours, to cellular response to DNA damage stimulus most significantly through DNA repair genes FANCG, BLM, and H2AFX. Comet assays demonstrated that 10μM iron treatment elicited DNA damage within 1 hour. This was accompanied by a brisk DNA damage response pulse, as ascertained by the development of DNA damage response (DDR) foci, and p53 stabilization.These data suggest that low dose iron treatments are sufficient to modify the vascular endothelium, and induce a DNA damage response.
Keywords	Medicine ; R ; Science ; Q
Subject code	612
Language	English
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Elevated factor VIII in hereditary haemorrhagic telangiectasia (HHT): association with venous thromboembolism.

Shovlin, Claire L / Sulaiman, N Laila / Govani, Fatima S / Jackson, James E / Begbie, Megan E

Thrombosis and haemostasis

2007 Volume 98, Issue 5, Page(s) 1031–1039

Abstract: Hereditary haemorrhagic telangiectasia (HHT) causes chronic nasal and gastrointestinal haemorrhage. Prothrombotic agents are commonly used for severe haemorrhage. Thrombotic risks have not been defined. In order to identify prothrombotic variables in HHT ...

Abstract	Hereditary haemorrhagic telangiectasia (HHT) causes chronic nasal and gastrointestinal haemorrhage. Prothrombotic agents are commonly used for severe haemorrhage. Thrombotic risks have not been defined. In order to identify prothrombotic variables in HHT patients, and assess their potential functional significance, a pilot ELISA-based study comparing plasma proteins in healthy individuals with HHT to age/sex-matched non-HHT controls was validated in a full study of 309 consecutive HHT-affected individuals. In the pilot study, factor VIII (FVIII) and von Willebrand factor antigen concentrations were elevated in the HHT group compared to non-HHT controls (p<0.0013, Mann-Whitney). Service laboratory measurements confirmed high FVIII:Ag in 125 HHT-affected individuals with no recent ill-health, intervention or venous thromboemboli. FVIII:Ag levels increased with age. Logistic regression also suggested an age-independent association with HHT-associated pulmonary arteriovenous malformations (AVMs). No association was demonstrated between FVIII:Ag and acute phase response, disseminated intravascular coagulation, ABO group, pulmonary artery pressure, or markers of HHT haemorrhage. Elevated FVIII:Ag were associated with shortened activated partial thromboplastin times (APTTs), and VTE:VTE affected 20/309 (6.5%) HHT-affected individuals, at median age 61(36-71) years. Four VTE occurred in factorV Leiden heterozygotes in the months following PAVM-associated brain abscess. The strongest association with VTE was with log-transformed FVIII:Ag measured 10-132 months from VTE (odds ratio 2.41, 95% confidence intervals 1.254, 4.612, p=0.008). Age made no additional contribution to VTE risk once adjusted for FVIII:Ag. In conclusion, HHT-related elevation of FVIII:Ag levels may influence thrombotic risk in HHT. Individualised risk-benefit considerations may be helpful in HHT management.
MeSH term(s)	Adult ; Aged ; Case-Control Studies ; Enzyme-Linked Immunosorbent Assay ; Factor VIII/analysis ; Female ; Humans ; Male ; Middle Aged ; Odds Ratio ; Regression Analysis ; Risk Factors ; Telangiectasia, Hereditary Hemorrhagic/blood ; Telangiectasia, Hereditary Hemorrhagic/complications ; Up-Regulation ; Venous Thromboembolism/etiology ; von Willebrand Factor/analysis
Chemical Substances	von Willebrand Factor ; Factor VIII (9001-27-8)
Language	English
Publishing date	2007-11
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	518294-3
ISSN	0340-6245
ISSN	0340-6245
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Uh III Zs.192: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Foxn1 regulates key target genes essential for T cell development in postnatal thymic epithelial cells.

Žuklys, Saulius / Handel, Adam / Zhanybekova, Saule / Govani, Fatima / Keller, Marcel / Maio, Stefano / Mayer, Carlos E / Teh, Hong Ying / Hafen, Katrin / Gallone, Giuseppe / Barthlott, Thomas / Ponting, Chris P / Holländer, Georg A

Nature immunology

2016 Volume 17, Issue 10, Page(s) 1206–1215

Abstract: Thymic epithelial cell differentiation, growth and function depend on the expression of the transcription factor Foxn1; however, its target genes have never been physically identified. Using static and inducible genetic model systems and chromatin ... ...

Abstract	Thymic epithelial cell differentiation, growth and function depend on the expression of the transcription factor Foxn1; however, its target genes have never been physically identified. Using static and inducible genetic model systems and chromatin studies, we developed a genome-wide map of direct Foxn1 target genes for postnatal thymic epithelia and defined the Foxn1 binding motif. We determined the function of Foxn1 in these cells and found that, in addition to the transcriptional control of genes involved in the attraction and lineage commitment of T cell precursors, Foxn1 regulates the expression of genes involved in antigen processing and thymocyte selection. Thus, critical events in thymic lympho-stromal cross-talk and T cell selection are indispensably choreographed by Foxn1.
MeSH term(s)	Animals ; Antigen Presentation/genetics ; Cell Communication ; Cell Differentiation/genetics ; Cell Lineage/genetics ; Cells, Cultured ; Clonal Selection, Antigen-Mediated/genetics ; Epithelial Cells/physiology ; Forkhead Transcription Factors/genetics ; Forkhead Transcription Factors/metabolism ; Gene Expression Regulation ; Genome/genetics ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Mice, Transgenic ; Precursor Cells, T-Lymphoid/physiology ; T-Lymphocytes/physiology ; Thymus Gland/physiology
Chemical Substances	Forkhead Transcription Factors ; Whn protein
Language	English
Publishing date	2016-08-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2016987-5
ISSN	1529-2916 ; 1529-2908
ISSN (online)	1529-2916
ISSN	1529-2908
DOI	10.1038/ni.3537
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Zs.A 5294: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 42: Show issues

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Article: Elevated factor VIII in hereditary haemorrhagic telangiectasia (HHT): Association with venous thromboembolism

Shovlin, Claire L. / Sulaiman, Laila N. / Govani, Fatima S. / Jackson, James E. / Begbie, Megan E.

Thrombosis and Haemostasis

2007 Volume 97, Issue 11, Page(s) 1031–1039

Abstract	Hereditary haemorrhagic telangiectasia (HHT) causes chronic nasal and gastrointestinal haemorrhage. Prothrombotic agents are commonly used for severe haemorrhage. Thrombotic risks have not been defined. In order to identify prothrombotic variables in HHT patients, and assess their potential functional significance, a pilot ELISA-based study comparing plasma proteins in healthy individuals with HHT to age/sex-matched non-HHT controls was validated in a full study of 309 consecutive HHTaffected individuals. In the pilot study, factor VIII (FVIII) and von Willebrand factor antigen concentrations were elevated in the HHT group compared to non-HHT controls (p<0.0013, Mann- Whitney). Service laboratory measurements confirmed high FVIII:Ag in 125 HHT-affected individuals with no recent illhealth, intervention or venous thromboemboli. FVIII:Ag levels increased with age. Logistic regression also suggested an age-independent association with HHT-associated pulmonary arteriovenous malformations (AVMs). No association was demonstrated between FVIII:Ag and acute phase response, disseminated intravascular coagulation, ABO group, pulmonary artery pressure, or markers of HHT haemorrhage. Elevated FVIII:Ag were associated with shortened activated partial thromboplastin times (APTTs), andVTE:VTE affected 20/309 (6.5%) HHT-affected individuals, at median age 61(36–71) years. Four VTE occurred in factorV Leiden heterozygotes in the months following PAVM-associated brain abscess. The strongest association with VTE was with log-transformed FVIII:Ag measured 10–132 months from VTE (odds ratio 2.41, 95% confidence intervals 1.254, 4.612, p=0.008). Age made no additional contribution to VTE risk once adjusted for FVIII:Ag. In conclusion, HHT-related elevation of FVIII:Ag levels may influence thrombotic risk in HHT. Individualised risk-benefit considerations may be helpful in HHT management.
Keywords	Brain abscess ; DIC ; pulmonary AVMs ; tranexamic acid ; VWF
Language	English
Publishing date	2007-01-01
Publisher	Schattauer GmbH
Publishing place	Stuttgart ; New York
Document type	Article
ZDB-ID	518294-3
ISSN	2567-689X ; 0340-6245
ISSN (online)	2567-689X
ISSN	0340-6245
DOI	10.1160/TH07-01-0064
Database	Thieme publisher's database

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Uh III Zs.192: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Endothelial cell processing and alternatively spliced transcripts of factor VIII: potential implications for coagulation cascades and pulmonary hypertension.

Shovlin, Claire L / Angus, Gillian / Manning, Richard A / Okoli, Grace N / Govani, Fatima S / Elderfield, Kay / Birdsey, Graeme M / Mollet, Inês G / Laffan, Michael A / Mauri, Francesco A

PloS one

2010 Volume 5, Issue 2, Page(s) e9154

Abstract: Background: Coagulation factor VIII (FVIII) deficiency leads to haemophilia A. Conversely, elevated plasma levels are a strong predictor of recurrent venous thromboemboli and pulmonary hypertension phenotypes in which in situ thromboses are implicated. ... ...

Abstract	Background: Coagulation factor VIII (FVIII) deficiency leads to haemophilia A. Conversely, elevated plasma levels are a strong predictor of recurrent venous thromboemboli and pulmonary hypertension phenotypes in which in situ thromboses are implicated. Extrahepatic sources of plasma FVIII are implicated, but have remained elusive. Methodology/principal findings: Immunohistochemistry of normal human lung tissue, and confocal microscopy, flow cytometry, and ELISA quantification of conditioned media from normal primary endothelial cells were used to examine endothelial expression of FVIII and coexpression with von Willebrand Factor (vWF), which protects secreted FVIII heavy chain from rapid proteloysis. FVIII transcripts predicted from database mining were identified by RT-PCR and sequencing. FVIII mAb-reactive material was demonstrated in CD31+ endothelial cells in normal human lung tissue, and in primary pulmonary artery, pulmonary microvascular, and dermal microvascular endothelial cells. In pulmonary endothelial cells, this protein occasionally colocalized with vWF, centered on Weibel Palade bodies. Pulmonary artery and pulmonary microvascular endothelial cells secreted low levels of FVIII and vWF to conditioned media, and demonstrated cell surface expression of FVIII and vWF Ab-reacting proteins compared to an isotype control. Four endothelial splice isoforms were identified. Two utilize transcription start sites in alternate 5' exons within the int22h-1 repeat responsible for intron 22 inversions in 40% of severe haemophiliacs. A reciprocal relationship between the presence of short isoforms and full-length FVIII transcript suggested potential splice-switching mechanisms. Conclusions/significance: The pulmonary endothelium is confirmed as a site of FVIII secretion, with evidence of synthesis, cell surface expression, and coexpression with vWF. There is complex alternate transcription initiation from the FVIII gene. These findings provide a framework for future research on the regulation and perturbation of FVIII synthesis, and of potential relevance to haemophilia, thromboses, and pulmonary hypertensive states.
MeSH term(s)	Alternative Splicing ; Base Sequence ; Blood Coagulation ; Cells, Cultured ; Endothelial Cells/cytology ; Endothelial Cells/metabolism ; Enzyme-Linked Immunosorbent Assay ; Exons/genetics ; Factor VIII/genetics ; Factor VIII/metabolism ; Flow Cytometry ; Humans ; Hypertension, Pulmonary/genetics ; Hypertension, Pulmonary/metabolism ; Immunohistochemistry ; Lung/blood supply ; Lung/cytology ; Lung/metabolism ; Microscopy, Confocal ; Protein Isoforms/genetics ; Protein Isoforms/metabolism ; Pulmonary Artery/cytology ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction ; Transcription Initiation Site ; Transcription, Genetic/genetics ; von Willebrand Factor/metabolism
Chemical Substances	Protein Isoforms ; von Willebrand Factor ; Factor VIII (9001-27-8)
Language	English
Publishing date	2010-02-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0009154
Database	MEDical Literature Analysis and Retrieval System OnLINE

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