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Article ; Online: Can MRI T

Spencer, Nicholas G / Lovell, David P / Elderfield, Kay / Austen, Brian / Howe, Franklyn A

2017 Volume 30, Issue 2, Page(s) 153–163

Abstract: Objectives: In the present study, we have tested whether MRI T: Materials and methods: 5xFAD and wild-type mice were imaged in a 4.7 T Varian horizontal bore MRI system to generate T: Results: In comparison with age-matched wild-type mice, we ... ...

Abstract	Objectives: In the present study, we have tested whether MRI T Materials and methods: 5xFAD and wild-type mice were imaged in a 4.7 T Varian horizontal bore MRI system to generate T Results: In comparison with age-matched wild-type mice, we observed first signs of amyloidosis in 2.5-month-old 5xFAD mice, and development of gliosis in 5-month-old 5xFAD mice. In contrast, MRI T Conclusions: In summary, our data suggest that MRI T
MeSH term(s)	Alzheimer Disease/diagnostic imaging ; Amyloid beta-Peptides/metabolism ; Animals ; Brain/diagnostic imaging ; Calcium-Binding Proteins/metabolism ; Corpus Callosum/diagnostic imaging ; Disease Models, Animal ; Disease Progression ; Female ; Glial Fibrillary Acidic Protein/metabolism ; Magnetic Resonance Imaging ; Male ; Mice ; Mice, Transgenic ; Microfilament Proteins/metabolism ; Sensorimotor Cortex/diagnostic imaging
Chemical Substances	Aif1 protein, mouse ; Amyloid beta-Peptides ; Calcium-Binding Proteins ; Glial Fibrillary Acidic Protein ; Microfilament Proteins
Language	English
Publishing date	2017-04
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1160826-2
ISSN	1352-8661 ; 0968-5243
ISSN (online)	1352-8661
ISSN	0968-5243
DOI	10.1007/s10334-016-0593-9
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Zs.A 3788: Show issues

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Article ; Online: Neuropathology of White Matter Lesions, Blood-Brain Barrier Dysfunction, and Dementia.

Hainsworth, Atticus H / Minett, Thais / Andoh, Joycelyn / Forster, Gillian / Bhide, Ishaan / Barrick, Thomas R / Elderfield, Kay / Jeevahan, Jamuna / Markus, Hugh S / Bridges, Leslie R

Stroke

2017 Volume 48, Issue 10, Page(s) 2799–2804

Abstract: Background and purpose: We tested whether blood-brain barrier dysfunction in subcortical white matter is associated with white matter abnormalities or risk of clinical dementia in older people (n=126; mean age 86.4, SD: 7.7 years) in the MRC CFAS ( ... ...

Abstract	Background and purpose: We tested whether blood-brain barrier dysfunction in subcortical white matter is associated with white matter abnormalities or risk of clinical dementia in older people (n=126; mean age 86.4, SD: 7.7 years) in the MRC CFAS (Medical Research Council Cognitive Function and Ageing Study). Methods: Using digital pathology, we quantified blood-brain barrier dysfunction (defined by immunohistochemical labeling for the plasma marker fibrinogen). This was assessed within subcortical white matter tissue samples harvested from postmortem T Results: Extent of fibrinogen labeling was not significantly associated with white matter abnormalities defined either by MRI (odds ratio, 0.90; 95% confidence interval, 0.79-1.03; Conclusions: Our data suggest that some degree of blood-brain barrier dysfunction is common in older people and that this may be related to clinical dementia risk, additional to standard MRI biomarkers.
MeSH term(s)	Aged ; Aged, 80 and over ; Blood-Brain Barrier/pathology ; Blood-Brain Barrier/physiopathology ; Dementia/pathology ; Dementia/physiopathology ; Female ; Humans ; Longitudinal Studies ; Magnetic Resonance Imaging/methods ; Male ; Prospective Studies ; White Matter/pathology ; White Matter/physiopathology
Language	English
Publishing date	2017-08-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80381-9
ISSN	1524-4628 ; 0039-2499 ; 0749-7954
ISSN (online)	1524-4628
ISSN	0039-2499 ; 0749-7954
DOI	10.1161/STROKEAHA.117.018101
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Zs.A 448: Show issues

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Article ; Online: Double-labelling immunohistochemistry for MGMT and a "cocktail" of non-tumourous elements is a reliable, quick and easy technique for inferring methylation status in glioblastomas and other primary brain tumours.

Burke, Elinor / Grobler, Mariana / Elderfield, Kay / Bond, Frances / Crocker, Matthew / Taylor, Rohan / Bridges, Leslie R

Acta neuropathologica communications

2013 Volume 1, Page(s) 22

Abstract: Background: Our aim was to develop a new protocol for MGMT immunohistochemistry with good agreement between observers and good correlation with molecular genetic tests of tumour methylation. We examined 40 primary brain tumours (30 glioblastomas and 10 ... ...

Abstract	Background: Our aim was to develop a new protocol for MGMT immunohistochemistry with good agreement between observers and good correlation with molecular genetic tests of tumour methylation. We examined 40 primary brain tumours (30 glioblastomas and 10 oligodendroglial tumours) with our new technique, namely double-labelling immunohistochemistry for MGMT and a "cocktail" of non-tumour antigens (CD34, CD45 and CD68). We compared the results with single-labelling immunohistochemistry for MGMT and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA, a recognised molecular genetic technique which we applied as the gold-standard for the methylation status). Results: Double-labelling immunohistochemistry for MGMT produced a visual separation of tumourous and non-tumourous elements on the same histological slide, making it quick and easy to determine whether tumour cell nuclei were MGMT-positive or MGMT-negative (and thereby infer the methylation status of the tumour). We found good agreement between observers (kappa 0.76) and within observer (kappa 0.84). Furthermore, double-labelling showed good specificity (80%), sensitivity (73.33%), positive predictive value (PPV, 83.33%) and negative predictive value (NPV, 68.75%) compared to MS-MLPA. Double-labelling was quicker and easier to assess than single-labelling and it outperformed quantitative computerised image analysis of MGMT single-labelling in terms of sensitivity, specificity, PPV and NPV. Conclusions: Double-labelling immunohistochemistry for MGMT and a cocktail of non-tumourous elements provides a "one look" method for determining whether tumour cell nuclei are MGMT-positive or MGMT-negative. This can be used to infer the methylation status of the tumour. There is good observer agreement and good specificity, sensitivity, PPV and NPV compared to a molecular gold-standard.
MeSH term(s)	Antigens, CD/metabolism ; Antigens, CD34/metabolism ; Antigens, Differentiation, Myelomonocytic/metabolism ; Brain Neoplasms/metabolism ; DNA Modification Methylases/metabolism ; DNA Repair Enzymes/metabolism ; False Negative Reactions ; False Positive Reactions ; Glioblastoma/metabolism ; Humans ; Immunohistochemistry/methods ; Leukocyte Common Antigens/metabolism ; Methylation ; Oligodendroglioma/metabolism ; Photomicrography ; Retrospective Studies ; Sensitivity and Specificity ; Tumor Suppressor Proteins/metabolism
Chemical Substances	Antigens, CD ; Antigens, CD34 ; Antigens, Differentiation, Myelomonocytic ; CD68 antigen, human ; Tumor Suppressor Proteins ; DNA Modification Methylases (EC 2.1.1.-) ; MGMT protein, human (EC 2.1.1.63) ; Leukocyte Common Antigens (EC 3.1.3.48) ; PTPRC protein, human (EC 3.1.3.48) ; DNA Repair Enzymes (EC 6.5.1.-)
Language	English
Publishing date	2013-06-10
Publishing country	England
Document type	Journal Article ; Validation Study
ZDB-ID	2715589-4
ISSN	2051-5960 ; 2051-5960
ISSN (online)	2051-5960
ISSN	2051-5960
DOI	10.1186/2051-5960-1-22
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Article: Bcl-6 and c-Myc are rarely co-expressed in adult diffuse large B-cell lymphoma.

Wagner, Simon D / Amen, Furrat / Trivedi, Pritesh S / Horncastle, Donna / Elderfield, Kay / Naresh, Kikkeri N

Leukemia & lymphoma

2007 Volume 48, Issue 8, Page(s) 1510–1513

Abstract: Bcl-6 is expressed in germinal centre derived B-cell non-Hodgkin lymphomas including diffuse large B-cell lymphoma (DLBCL) and is likely to play a major role in driving proliferation of a subset of DLBCLs, especially those of germinal centre B-cell ... ...

Abstract	Bcl-6 is expressed in germinal centre derived B-cell non-Hodgkin lymphomas including diffuse large B-cell lymphoma (DLBCL) and is likely to play a major role in driving proliferation of a subset of DLBCLs, especially those of germinal centre B-cell subtype, but the role of c-Myc, which is important for proliferation in various lineages is not known. We used the highly standardised staining conditions of a tissue microarray to characterise co-expression of c-Myc and Bcl-6 in DLBCL. We carried out immunohistochemistry of 73 arrayed cases. The majority (62/73) did not express c-Myc, but 11 cases (15%) showed nuclear staining. 5/53 (9%) of Bcl-6 expressing cases co-expressed c-Myc, whereas a much higher proportion, 6/20 (30%), of Bcl-6 negative cases were positive for c-Myc. Overall survival of c-Myc expressing cases was the same as those that had absent expression. There was no significant correlation between c-Myc expression and DLBCL subtype (germinal centre or non-germinal centre subtypes).
MeSH term(s)	Adult ; Germinal Center/metabolism ; Germinal Center/pathology ; Humans ; Immunoenzyme Techniques ; Lymphoma, B-Cell/metabolism ; Lymphoma, B-Cell/pathology ; Lymphoma, Large B-Cell, Diffuse/metabolism ; Lymphoma, Large B-Cell, Diffuse/pathology ; Proto-Oncogene Proteins c-bcl-6/metabolism ; Proto-Oncogene Proteins c-myc/metabolism ; Tissue Array Analysis
Chemical Substances	Proto-Oncogene Proteins c-bcl-6 ; Proto-Oncogene Proteins c-myc
Language	English
Publishing date	2007-08-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	1042374-6
ISSN	1029-2403 ; 1042-8194
ISSN (online)	1029-2403
ISSN	1042-8194
DOI	10.1080/10428190701458491
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Zs.A 2997: Show issues

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Article ; Online: Phenotype of blasts in chronic myeloid leukemia in blastic phase-Analysis of bone marrow trephine biopsies and correlation with cytogenetics.

Reid, Alistair G / De Melo, Valeria A / Elderfield, Kay / Clark, Ian / Marin, David / Apperley, Jane / Naresh, Kikkeri N

Leukemia research

2009 Volume 33, Issue 3, Page(s) 418–425

Abstract: We identified different phenotypic subsets among 62 cases of chronic myeloid leukemia (CML) in blast crisis (BC) (26% B-lymphoblastic, and 74% various myeloblastic subsets) on bone marrow trephines and correlated the blast-phenotype with cytogenetics. ... ...

Abstract	We identified different phenotypic subsets among 62 cases of chronic myeloid leukemia (CML) in blast crisis (BC) (26% B-lymphoblastic, and 74% various myeloblastic subsets) on bone marrow trephines and correlated the blast-phenotype with cytogenetics. Five of myeloid-BC had an associated 3q26 abnormality and two of these showed a megakaryoblastic-phenotype. While myeloid-BC was associated with additional copies of Philadelphia (Ph) (29%) (p=0.08), numerical abnormalities (51%) (p=0.007), trisomy-8 (29%) (p=0.08) and 17p-loss (22%), none of lymphoid-BC showed these abnormalities. Among myeloid-BC, CD34-negative cases were more often associated with trisomy-8, 17p-loss and numerical abnormalities, and the CD117-negative subset with additional copies of Ph (p<0.05).
MeSH term(s)	Biopsy ; Blast Crisis/genetics ; Blast Crisis/pathology ; Bone Marrow/pathology ; Chromosome Aberrations ; Cytogenetic Analysis ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology ; Phenotype ; Retrospective Studies
Language	English
Publishing date	2009-03
Publishing country	England
Document type	Journal Article
ZDB-ID	752396-8
ISSN	1873-5835 ; 0145-2126
ISSN (online)	1873-5835
ISSN	0145-2126
DOI	10.1016/j.leukres.2008.07.019
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Zs.A 1321: Show issues

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Article ; Online: Coronary intraplaque hemorrhage evokes a novel atheroprotective macrophage phenotype.

Boyle, Joseph J / Harrington, Heather A / Piper, Emma / Elderfield, Kay / Stark, Jaroslav / Landis, Robert C / Haskard, Dorian O

The American journal of pathology

2009 Volume 174, Issue 3, Page(s) 1097–1108

Abstract: Intraplaque hemorrhage accelerates atherosclerosis via oxidant stress and contributes to lesion development and destabilization. Normally, macrophages scavenge hemoglobin-haptoglobin (HbHp) complexes via CD163, and this process provokes the secretion of ... ...

Abstract	Intraplaque hemorrhage accelerates atherosclerosis via oxidant stress and contributes to lesion development and destabilization. Normally, macrophages scavenge hemoglobin-haptoglobin (HbHp) complexes via CD163, and this process provokes the secretion of the anti-inflammatory atheroprotective cytokine interleukin (IL)-10. We therefore tested the hypothesis that HbHp complexes may drive monocyte differentiation to an atheroprotective phenotype. Examination of the macrophage phenotype in hemorrhaged atherosclerotic plaques revealed a novel hemorrhage-associated macrophage population (HA-mac), defined by high levels of CD163, but low levels of human leukocyte antigen-DR. HA-mac contained more iron, a pro-oxidant catalyst, but paradoxically had less oxidative injury, measured by 8-oxo-guanosine content. Differentiating monocytes with HbHp complexes reproduced the CD163(high) human leukocyte antigen-DR(low) HA-mac phenotype in vitro. These in vitro HA-mac cells cleared Hb more quickly, and consistently showed less hydrogen peroxide release, highly reactive oxygen species and oxidant stress, and increased survival. Differentiation to HA-mac was prevented by neutralizing IL-10 antibodies, indicating that IL-10 mediates an autocrine feedback mechanism in this system. Nonlinear dynamic modeling showed that an IL-10/CD163-positive feedback loop drove a discrete HA-mac lineage. Simulations further indicated an all-or-none switch to HA-mac at threshold levels of HbHp, and this conversion was experimentally verified. These data demonstrate the creation of a novel atheroprotective (HA-mac) macrophage subpopulation in response to intraplaque hemorrhage and raise the possibility that therapeutically reproducing this macrophage phenotype may be cardio-protective in cases of atherosclerosis.
MeSH term(s)	Antigens, CD/analysis ; Antigens, Differentiation, Myelomonocytic/analysis ; Atherosclerosis/genetics ; Atherosclerosis/prevention & control ; Autopsy ; Coronary Stenosis/complications ; Coronary Stenosis/pathology ; Hemorrhage/pathology ; Humans ; Macrophages/pathology ; Microscopy, Confocal ; Monocytes/pathology ; Monocytes/physiology ; Oxidative Stress ; Phenotype ; Receptors, Cell Surface/analysis
Chemical Substances	Antigens, CD ; Antigens, Differentiation, Myelomonocytic ; CD163 antigen ; Receptors, Cell Surface
Language	English
Publishing date	2009-02-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2943-9
ISSN	1525-2191 ; 0002-9440
ISSN (online)	1525-2191
ISSN	0002-9440
DOI	10.2353/ajpath.2009.080431
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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
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Article ; Online: Can MRI T

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Article ; Online: Neuropathology of White Matter Lesions, Blood-Brain Barrier Dysfunction, and Dementia.

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Article ; Online: Double-labelling immunohistochemistry for MGMT and a "cocktail" of non-tumourous elements is a reliable, quick and easy technique for inferring methylation status in glioblastomas and other primary brain tumours.

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Article: Bcl-6 and c-Myc are rarely co-expressed in adult diffuse large B-cell lymphoma.

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Article ; Online: Phenotype of blasts in chronic myeloid leukemia in blastic phase-Analysis of bone marrow trephine biopsies and correlation with cytogenetics.

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Article ; Online: Coronary intraplaque hemorrhage evokes a novel atheroprotective macrophage phenotype.

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Article ; Online: Endothelial cell processing and alternatively spliced transcripts of factor VIII: potential implications for coagulation cascades and pulmonary hypertension.

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