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Article ; Online: Fibroblast Foci and Patchy Fibrosis Do Not Separate Usual Interstitial Pneumonia From Fibrotic Hypersensitivity Pneumonitis in Transbronchial Cryobiopsies.

Churg, Andrew / Ryerson, Christopher J / Wright, Joanne L

Archives of pathology & laboratory medicine

2021 Volume 145, Issue 11, Page(s) 1325–1326

MeSH term(s)	Alveolitis, Extrinsic Allergic/diagnosis ; Alveolitis, Extrinsic Allergic/etiology ; Fibroblasts ; Fibrosis ; Humans ; Idiopathic Pulmonary Fibrosis/diagnosis
Language	English
Publishing date	2021-10-21
Publishing country	United States
Document type	Letter ; Comment
ZDB-ID	194119-7
ISSN	1543-2165 ; 0363-0153 ; 0096-8528 ; 0003-9985
ISSN (online)	1543-2165
ISSN	0363-0153 ; 0096-8528 ; 0003-9985
DOI	10.5858/arpa.2021-0234-LE
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Article ; Online: Morphologic Features of Fibrotic Hypersensitivity Pneumonitis in Transbronchial Cryobiopsies Versus Video-Assisted Thoracoscopic Biopsies: An In Silico Study.

Churg, Andrew / Wright, Joanne L

Archives of pathology & laboratory medicine

2020 Volume 145, Issue 4, Page(s) 448–452

Abstract: Context.—: There is interest in using transbronchial cryobiopsies (CBs) for the diagnosis of fibrotic (chronic) hypersensitivity pneumonitis (FHP), but with little information in the literature about what features are diagnostic in CBs.: Objective.—: ...

Abstract	Context.—: There is interest in using transbronchial cryobiopsies (CBs) for the diagnosis of fibrotic (chronic) hypersensitivity pneumonitis (FHP), but with little information in the literature about what features are diagnostic in CBs. Objective.—: To determine, using in silico investigation, whether features supporting a diagnosis of FHP in video-assisted thoracoscopic (VATS) biopsies can be identified in CBs. Design.—: In silico circular "cryobiopsies," 5.25 mm in diameter (21.6 mm2), were created on the slides of 15 VATS biopsy cases that had been assigned a 60% or greater confident diagnosis of FHP at a specially devised multidisciplinary discussion. Using stratified random sampling, up to 8 "cryobiopsies" per case were analyzed for the presence of giant cells/granulomas or peribronchiolar metaplasia affecting 50% or more of the bronchioles, features that had statistically supported a diagnosis of FHP on the VATS biopsies in the multidisciplinary discussion exercise. Results.—: Giant cells/granulomas were detected with very low sensitivities in the "cryobiopsies." Using peribronchiolar metaplasia in 50% or more of bronchioles alone, the sensitivity/specificity for a diagnosis of FHP of 2 "cryobiopsies" compared to the corresponding VATS biopsy was 0.57/0.63; for 4 "cryobiopsies," 0.86/0.75; and for 8 "cryobiopsies," 0.83/0.71. Adding giant cells/granulomas slightly improved these numbers to 0.63/0.71 for 2 "cryobiopsies"; 1.00/0.86 for 4; and 1.00/0.80 for 8. Conclusions.—: In the setting of a multidisciplinary discussion where FHP is part of the differential diagnostic choices, 4 actual CBs with an area of roughly 20 mm2 each should have good sensitivity and reasonable specificity for diagnosing FHP using these specific morphologic criteria.
MeSH term(s)	Alveolitis, Extrinsic Allergic/pathology ; Biopsy ; Cross-Sectional Studies ; Cryosurgery ; Humans ; Lung/pathology ; Predictive Value of Tests ; Pulmonary Fibrosis/pathology ; Reproducibility of Results ; Retrospective Studies ; Thoracic Surgery, Video-Assisted
Language	English
Publishing date	2020-09-17
Publishing country	United States
Document type	Comparative Study ; Journal Article
ZDB-ID	194119-7
ISSN	1543-2165 ; 0363-0153 ; 0096-8528 ; 0003-9985
ISSN (online)	1543-2165
ISSN	0363-0153 ; 0096-8528 ; 0003-9985
DOI	10.5858/arpa.2020-0176-OA
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Article ; Online: Mathematical models of coagulation-are we there yet?

Owen, Matt J / Wright, Joy R / Tuddenham, Edward G D / King, John R / Goodall, Alison H / Dunster, Joanne L

Journal of thrombosis and haemostasis : JTH

2024

Abstract: Background: Mathematical models of coagulation have been developed to mirror thrombin generation in plasma, with the aim of investigating how variation in coagulation factor levels regulates hemostasis. However, current models vary in the reactions they ...

Abstract	Background: Mathematical models of coagulation have been developed to mirror thrombin generation in plasma, with the aim of investigating how variation in coagulation factor levels regulates hemostasis. However, current models vary in the reactions they capture and the reaction rates used, and their validation is restricted by a lack of large coherent datasets, resulting in questioning of their utility. Objectives: To address this debate, we systematically assessed current models against a large dataset, using plasma coagulation factor levels from 348 individuals with normal hemostasis to identify the causes of these variations. Methods: We compared model predictions with measured thrombin generation, quantifying and comparing the ability of each model to predict thrombin generation, the contributions of the individual reactions, and their dependence on reaction rates. Results: We found that no current model predicted the hemostatic response across the whole cohort and all produced thrombin generation curves that did not resemble those obtained experimentally. Our analysis has identified the key reactions that lead to differential model predictions, where experimental uncertainty leads to variability in predictions, and we determined reactions that have a high influence on measured thrombin generation, such as the contribution of factor XI. Conclusion: This systematic assessment of models of coagulation, using large dataset inputs, points to ways in which these models can be improved. A model that accurately reflects the effects of the multiple subtle variations in an individual's hemostatic profile could be used for assessing antithrombotics or as a tool for precision medicine.
Language	English
Publishing date	2024-03-21
Publishing country	England
Document type	Journal Article
ZDB-ID	2112661-6
ISSN	1538-7836 ; 1538-7933
ISSN (online)	1538-7836
ISSN	1538-7933
DOI	10.1016/j.jtha.2024.03.009
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Article: A System-Wide Investigation and Stratification of the Hemostatic Proteome in Premature Myocardial Infarction.

Dunster, Joanne L / Wright, Joy R / Samani, Nilesh J / Goodall, Alison H

Frontiers in cardiovascular medicine

2022 Volume 9, Page(s) 919394

Abstract: Introduction: Advancing understanding of key factors that determine the magnitude of the hemostatic response may facilitate the identification of individuals at risk of generating an occlusive thrombus as a result of an atherothrombotic event such as an ...

Abstract	Introduction: Advancing understanding of key factors that determine the magnitude of the hemostatic response may facilitate the identification of individuals at risk of generating an occlusive thrombus as a result of an atherothrombotic event such as an acute Myocardial Infarction (MI). While fibrinogen levels are a recognized risk factor for MI, the association of thrombotic risk with other coagulation proteins is inconsistent. This is likely due to the complex balance of pro- and anticoagulant factors in any individual. Methods: We compared measured levels of pro- and anticoagulant proteins in plasma from 162 patients who suffered an MI at an early age (MI <50 y) and 186 age- and gender-matched healthy controls with no history of CAD. We then used the measurements from these individuals as inputs for an established mathematical model to investigate how small variations in hemostatic factors affect the overall amplitude of the hemostatic response and to identify differential key drivers of the hemostatic response in male and female patients and controls. Results: Plasma from the MI patients contained significantly higher levels of Tissue Factor ( Conclusions: We suggest that modeling could be of value in enhancing our prediction of risk of premature MI, recurrent risk, and therapeutic efficacy.
Language	English
Publishing date	2022-06-30
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2781496-8
ISSN	2297-055X
ISSN	2297-055X
DOI	10.3389/fcvm.2022.919394
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Article ; Online: Use of Germline BRCA Testing in Patients With Ovarian Cancer and Commercial Insurance.

Cham, Stephanie / Landrum, Mary Beth / Keating, Nancy L / Armstrong, Joanne / Wright, Alexi A

JAMA network open

2022 Volume 5, Issue 1, Page(s) e2142703

MeSH term(s)	Aged ; Antineoplastic Agents/therapeutic use ; Cross-Sectional Studies ; Delayed Diagnosis ; Early Detection of Cancer ; Female ; Genes, Tumor Suppressor ; Genetic Testing/statistics & numerical data ; Humans ; Insurance, Health ; Middle Aged ; Ovarian Neoplasms/diagnosis ; Ovarian Neoplasms/drug therapy ; Ovarian Neoplasms/epidemiology ; Ovarian Neoplasms/genetics ; Practice Patterns, Physicians'
Chemical Substances	Antineoplastic Agents
Language	English
Publishing date	2022-01-04
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S.
ISSN	2574-3805
ISSN (online)	2574-3805
DOI	10.1001/jamanetworkopen.2021.42703
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Article ; Online: Exploiting lung adaptation and phage steering to clear pan-resistant Pseudomonas aeruginosa infections in vivo.

Ashworth, Eleri A / Wright, Rosanna C T / Shears, Rebecca K / Wong, Janet K L / Hassan, Akram / Hall, James P J / Kadioglu, Aras / Fothergill, Joanne L

Nature communications

2024 Volume 15, Issue 1, Page(s) 1547

Abstract: Pseudomonas aeruginosa is a major nosocomial pathogen that causes severe disease including sepsis. Carbapenem-resistant P. aeruginosa is recognised by the World Health Organisation as a priority 1 pathogen, with urgent need for new therapeutics. As such, ...

Abstract	Pseudomonas aeruginosa is a major nosocomial pathogen that causes severe disease including sepsis. Carbapenem-resistant P. aeruginosa is recognised by the World Health Organisation as a priority 1 pathogen, with urgent need for new therapeutics. As such, there is renewed interest in using bacteriophages as a therapeutic. However, the dynamics of treating pan-resistant P. aeruginosa with phage in vivo are poorly understood. Using a pan-resistant P. aeruginosa in vivo infection model, phage therapy displays strong therapeutic potential, clearing infection from the blood, kidneys, and spleen. Remaining bacteria in the lungs and liver displays phage resistance due to limiting phage adsorption. Yet, resistance to phage results in re-sensitisation to a wide range of antibiotics. In this work, we use phage steering in vivo, pre-exposing a pan resistant P. aeruginosa infection with a phage cocktail to re-sensitise bacteria to antibiotics, clearing the infection from all organs.
MeSH term(s)	Humans ; Bacteriophages ; Pseudomonas Infections/therapy ; Pseudomonas Infections/microbiology ; Lung/microbiology ; Anti-Bacterial Agents/pharmacology ; Anti-Bacterial Agents/therapeutic use ; Phage Therapy/methods ; Pseudomonas aeruginosa
Chemical Substances	Anti-Bacterial Agents
Language	English
Publishing date	2024-02-20
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-45785-z
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Article ; Online: A System-Wide Investigation and Stratification of the Hemostatic Proteome in Premature Myocardial Infarction

Joanne L. Dunster / Joy R. Wright / Nilesh J. Samani / Alison H. Goodall

Frontiers in Cardiovascular Medicine, Vol

2022 Volume 9

Abstract: IntroductionAdvancing understanding of key factors that determine the magnitude of the hemostatic response may facilitate the identification of individuals at risk of generating an occlusive thrombus as a result of an atherothrombotic event such as an ... ...

Abstract	IntroductionAdvancing understanding of key factors that determine the magnitude of the hemostatic response may facilitate the identification of individuals at risk of generating an occlusive thrombus as a result of an atherothrombotic event such as an acute Myocardial Infarction (MI). While fibrinogen levels are a recognized risk factor for MI, the association of thrombotic risk with other coagulation proteins is inconsistent. This is likely due to the complex balance of pro- and anticoagulant factors in any individual.MethodsWe compared measured levels of pro- and anticoagulant proteins in plasma from 162 patients who suffered an MI at an early age (MI <50 y) and 186 age- and gender-matched healthy controls with no history of CAD. We then used the measurements from these individuals as inputs for an established mathematical model to investigate how small variations in hemostatic factors affect the overall amplitude of the hemostatic response and to identify differential key drivers of the hemostatic response in male and female patients and controls.ResultsPlasma from the MI patients contained significantly higher levels of Tissue Factor (P = 0.007), the components of the tenase (FIX and FVIII; P < 0.0001 for both) and the prothrombinase complexes (FX; P = 0.003), and lower levels of Tissue Factor Pathway Inhibitor (TFPI; P = 0.033) than controls. The mathematical model, which generates time-dependent predictions describing the depletion, activation, and interaction of the main procoagulant factors and inhibitors, identified different patterns of hemostatic response between MI patients and controls, and additionally, between males and females. Whereas, in males, TF, FVIII, FIX, and the inhibitor TFPI contribute to the differences seen between case and controls, and in females, FII, FVIII, and FIX had the greatest influence on the generation of thrombin. We additionally show that further donor stratification may be possible according to the predicted donor response to anticoagulant therapy.ConclusionsWe ...
Keywords	computational biology ; coagulation ; thrombosis ; myocardial infarction ; clinical studies ; gender ; Diseases of the circulatory (Cardiovascular) system ; RC666-701
Subject code	610
Language	English
Publishing date	2022-06-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
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Article ; Online: The Pathology of Chronic Obstructive Pulmonary Disease: Progress in the 20th and 21st Centuries.

Berg, Kyra / Wright, Joanne L

Archives of pathology & laboratory medicine

2016 Volume 140, Issue 12, Page(s) 1423–1428

Abstract: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and is the fourth leading cause of death worldwide. There has been significant progress in the pathologic description and pathophysiologic analysis of COPD in the 20th and 21st ... ...

Abstract	Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and is the fourth leading cause of death worldwide. There has been significant progress in the pathologic description and pathophysiologic analysis of COPD in the 20th and 21st centuries. We review the history, progression, and significance of pathologic alterations in COPD, including emphysematous changes, airway alterations, and vascular alterations. We also indicate what pathologic features of COPD the practicing pathologist should be describing in standard surgical and autopsy specimens.
MeSH term(s)	Airway Resistance ; Animals ; Disease Progression ; Humans ; Lung/blood supply ; Lung/diagnostic imaging ; Lung/pathology ; Lung/physiopathology ; Lung Diseases, Interstitial/complications ; Parenchymal Tissue/blood supply ; Parenchymal Tissue/diagnostic imaging ; Parenchymal Tissue/pathology ; Parenchymal Tissue/physiopathology ; Pulmonary Circulation ; Pulmonary Disease, Chronic Obstructive/complications ; Pulmonary Disease, Chronic Obstructive/diagnosis ; Pulmonary Disease, Chronic Obstructive/pathology ; Pulmonary Disease, Chronic Obstructive/physiopathology ; Pulmonary Emphysema/etiology ; Severity of Illness Index ; Vascular Diseases/etiology
Language	English
Publishing date	2016-12
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	194119-7
ISSN	1543-2165 ; 0363-0153 ; 0096-8528 ; 0003-9985
ISSN (online)	1543-2165
ISSN	0363-0153 ; 0096-8528 ; 0003-9985
DOI	10.5858/arpa.2015-0455-RS
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Article ; Online: Chemoselective Methionine Labelling of Recombinant Trastuzumab Shows High In Vitro and In Vivo Tumour Targeting.

Hashad, Rania A / Jap, Edwina / Casey, Joanne L / Candace Ho, Y T / Wright, Alexander / Thalmann, Claudia / Sleeman, Mark / Lupton, David W / Hagemeyer, Christoph E / Cryle, Max J / Robert, Remy / Alt, Karen

Chemistry (Weinheim an der Bergstrasse, Germany)

2023 Volume 29, Issue 11, Page(s) e202202491

Abstract: A highly effective 2-step system for site-specific antibody modification and conjugation of the monoclonal antibody Herceptin (commercially available under Trastuzumab) in a cysteine-independent manner was used to generate labelled antibodies for in vivo ...

Abstract	A highly effective 2-step system for site-specific antibody modification and conjugation of the monoclonal antibody Herceptin (commercially available under Trastuzumab) in a cysteine-independent manner was used to generate labelled antibodies for in vivo imaging. The first step contains redox-activated chemical tagging (ReACT) of thioethers via engineered methionine residues to introduce specific alkyne moieties, thereby offering a novel easy way to fundamentally change the process of antibody bioconjugation. The second step involves modification of the introduced alkyne via azide-alkyne cycloaddition 'click' conjugation. The versatility of this 2-step approach is demonstrated here by the selective incorporation of a fluorescent dye but can also be applied to a wide variety of different conjugation partners depending on the desired application in a facile manner. Methionine-modified antibodies were characterised in vitro, and the diagnostic potential of the most promising variant was further analysed in an in vivo xenograft animal model using a fluorescence imaging modality. This study demonstrates how methionine-mediated antibody conjugation offers an orthogonal and versatile route to the generation of tailored antibody conjugates with in vivo applicability.
MeSH term(s)	Animals ; Humans ; Trastuzumab ; Methionine ; Antibodies, Monoclonal/chemistry ; Racemethionine ; Neoplasms ; Alkynes/chemistry ; Azides/chemistry
Chemical Substances	Trastuzumab (P188ANX8CK) ; Methionine (AE28F7PNPL) ; Antibodies, Monoclonal ; Racemethionine (73JWT2K6T3) ; Alkynes ; Azides
Language	English
Publishing date	2023-01-18
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1478547-X
ISSN	1521-3765 ; 0947-6539
ISSN (online)	1521-3765
ISSN	0947-6539
DOI	10.1002/chem.202202491
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Article ; Online: Cicatricial organising pneumonia mimicking a fibrosing interstitial pneumonia.

Churg, Andrew / Wright, Joanne L / Bilawich, AnaMaria

Histopathology

2018 Volume 72, Issue 5, Page(s) 846–854

Abstract: Aims: Organising pneumonia (OP) is composed of loose granulation tissue plugs in distal airspaces; these disappear with steroid treatment. Recently a variant labelled 'cicatricial' OP has been described in which the granulation tissue organised to much ... ...

Abstract	Aims: Organising pneumonia (OP) is composed of loose granulation tissue plugs in distal airspaces; these disappear with steroid treatment. Recently a variant labelled 'cicatricial' OP has been described in which the granulation tissue organised to much denser fibrous tissue but still retained the usual pattern of OP. Here we report 10 patients thought to have an interstitial lung disease, and who on biopsy had a variant of cicatricial OP characterised by linear bands or small nodular masses of dense fibrous tissue that does not resemble ordinary OP. Methods and results: The bands/nodules were usually distributed randomly but occasionally resembled fibrotic non-specific interstitial pneumonia in local areas. Small foci of loose granulation tissue at the edge of the fibrotic bands sometimes mimicked fibroblast foci. Recognisable conventional OP was always present, but often in very small amounts. Four cases, including one patient with Ehlers-Danlos syndrome, showed formation of bone in the fibrotic bands and nodules. On computerised tomography (CT) scan of the chest some cases looked like typical OP, but some demonstrated only irregularly distributed linear opacities, sometimes with associated calcification. Follow-up imaging on six cases showed that the process either markedly improved or remained stable over time; no case had progressive disease. Conclusions: Cicatricial OP with this pathological pattern represents an uncommon form of OP that appears to be a generally benign process which may have persisting linear opacities on CT scan but that does not progress; however, it can be confused on biopsy and CT with a fibrosing interstitial pneumonia.
MeSH term(s)	Adult ; Aged ; Cryptogenic Organizing Pneumonia/diagnosis ; Cryptogenic Organizing Pneumonia/pathology ; Diagnosis, Differential ; Female ; Fibrosis/diagnosis ; Fibrosis/pathology ; Humans ; Lung/pathology ; Lung Diseases, Interstitial/diagnosis ; Lung Diseases, Interstitial/pathology ; Male ; Middle Aged
Language	English
Publishing date	2018-01-29
Publishing country	England
Document type	Journal Article
ZDB-ID	131914-0
ISSN	1365-2559 ; 0309-0167
ISSN (online)	1365-2559
ISSN	0309-0167
DOI	10.1111/his.13443
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