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Article ; Online: Detection of endometrial cancer in cervico-vaginal fluid and blood plasma: leveraging proteomics and machine learning for biomarker discovery.

Njoku, Kelechi / Pierce, Andrew / Chiasserini, Davide / Geary, Bethany / Campbell, Amy E / Kelsall, Janet / Reed, Rachel / Geifman, Nophar / Whetton, Anthony D / Crosbie, Emma J

EBioMedicine

2024 Volume 102, Page(s) 105064

Abstract: Background: The anatomical continuity between the uterine cavity and the lower genital tract allows for the exploitation of uterine-derived biomaterial in cervico-vaginal fluid for endometrial cancer detection based on non-invasive sampling ... ...

Abstract	Background: The anatomical continuity between the uterine cavity and the lower genital tract allows for the exploitation of uterine-derived biomaterial in cervico-vaginal fluid for endometrial cancer detection based on non-invasive sampling methodologies. Plasma is an attractive biofluid for cancer detection due to its simplicity and ease of collection. In this biomarker discovery study, we aimed to identify proteomic signatures that accurately discriminate endometrial cancer from controls in cervico-vaginal fluid and blood plasma. Methods: Blood plasma and Delphi Screener-collected cervico-vaginal fluid samples were acquired from symptomatic post-menopausal women with (n = 53) and without (n = 65) endometrial cancer. Digitised proteomic maps were derived for each sample using sequential window acquisition of all theoretical mass spectra (SWATH-MS). Machine learning was employed to identify the most discriminatory proteins. The best diagnostic model was determined based on accuracy and model parsimony. Findings: A protein signature derived from cervico-vaginal fluid more accurately discriminated cancer from control samples than one derived from plasma. A 5-biomarker panel of cervico-vaginal fluid derived proteins (HPT, LG3BP, FGA, LY6D and IGHM) predicted endometrial cancer with an AUC of 0.95 (0.91-0.98), sensitivity of 91% (83%-98%), and specificity of 86% (78%-95%). By contrast, a 3-marker panel of plasma proteins (APOD, PSMA7 and HPT) predicted endometrial cancer with an AUC of 0.87 (0.81-0.93), sensitivity of 75% (64%-86%), and specificity of 84% (75%-93%). The parsimonious model AUC values for detection of stage I endometrial cancer in cervico-vaginal fluid and blood plasma were 0.92 (0.87-0.97) and 0.88 (0.82-0.95) respectively. Interpretation: Here, we leveraged the natural shed of endometrial tumours to potentially develop an innovative approach to endometrial cancer detection. We show proof of principle that endometrial cancers secrete unique protein signatures that can enable cancer detection via cervico-vaginal fluid assays. Confirmation in a larger independent cohort is warranted. Funding: Cancer Research UK, Blood Cancer UK, National Institute for Health Research.
MeSH term(s)	Humans ; Female ; Proteomics ; Endometrial Neoplasms/diagnosis ; Endometrial Neoplasms/pathology ; Biomarkers ; Plasma ; Machine Learning
Chemical Substances	Biomarkers
Language	English
Publishing date	2024-03-20
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2851331-9
ISSN	2352-3964
ISSN (online)	2352-3964
DOI	10.1016/j.ebiom.2024.105064
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Article ; Online: Differential expression of cyclin-dependent kinases in the adult human retina in relation to CDK inhibitor retinotoxicity.

Wright, Phillip / Kelsall, Janet / Healing, Guy / Sanderson, Julie

Archives of toxicology

2019 Volume 93, Issue 3, Page(s) 659–671

Abstract: Cyclin-dependent kinases (CDKs) are a family of kinases associated predominantly with cell cycle control, making CDK inhibitors interesting candidates for anti-cancer therapeutics. However, retinal toxicity (loss of photoreceptors) has been associated ... ...

Abstract	Cyclin-dependent kinases (CDKs) are a family of kinases associated predominantly with cell cycle control, making CDK inhibitors interesting candidates for anti-cancer therapeutics. However, retinal toxicity (loss of photoreceptors) has been associated with CDK inhibitors, including the pan-CDK inhibitor AG-012896. The purpose of this research was to use a novel planar sectioning technique to determine CDK expression profiles in the ex vivo human retina with the aim of identifying isoforms responsible for CDK retinotoxicity. Four CDK isoforms (CDK11, 16, 17 and 18) were selected as a result of IC
MeSH term(s)	Adult ; Benzamides/toxicity ; Bridged Bicyclo Compounds, Heterocyclic/toxicity ; Cell Cycle Checkpoints ; Cell Death/drug effects ; Cyclin-Dependent Kinases/metabolism ; Humans ; Protein Kinase Inhibitors/toxicity ; Pyridinium Compounds/toxicity ; Retina/drug effects ; Retina/physiology ; Thiazoles/toxicity ; Toxicity Tests
Chemical Substances	AG-012986 ; Benzamides ; Bridged Bicyclo Compounds, Heterocyclic ; Protein Kinase Inhibitors ; Pyridinium Compounds ; Thiazoles ; dinaciclib (4V8ECV0NBQ) ; Cyclin-Dependent Kinases (EC 2.7.11.22)
Language	English
Publishing date	2019-01-08
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	124992-7
ISSN	1432-0738 ; 0340-5761
ISSN (online)	1432-0738
ISSN	0340-5761
DOI	10.1007/s00204-018-2376-8
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Article: A Prostate Cancer Proteomics Database for SWATH-MS Based Protein Quantification.

Muazzam, Ammara / Chiasserini, Davide / Kelsall, Janet / Geifman, Nophar / Whetton, Anthony D / Townsend, Paul A

Cancers

2021 Volume 13, Issue 21

Abstract: Prostate cancer is the most frequent form of cancer in men, accounting for more than one-third of all cases. Current screening techniques, such as PSA testing used in conjunction with routine procedures, lead to unnecessary biopsies and the discovery of ... ...

Abstract	Prostate cancer is the most frequent form of cancer in men, accounting for more than one-third of all cases. Current screening techniques, such as PSA testing used in conjunction with routine procedures, lead to unnecessary biopsies and the discovery of low-risk tumours, resulting in overdiagnosis. SWATH-MS is a well-established data-independent (DI) method requiring prior knowledge of targeted peptides to obtain valuable information from SWATH maps. In response to the growing need to identify and characterise protein biomarkers for prostate cancer, this study explored a spectrum source for targeted proteome analysis of blood samples. We created a comprehensive prostate cancer serum spectral library by combining data-dependent acquisition (DDA) MS raw files from 504 patients with low, intermediate, or high-grade prostate cancer and healthy controls, as well as 304 prostate cancer-related protein in silico assays. The spectral library contains 114,684 transitions, which equates to 18,479 peptides translated into 1227 proteins. The robustness and accuracy of the spectral library were assessed to boost confidence in the identification and quantification of prostate cancer-related proteins across an independent cohort, resulting in the identification of 404 proteins. This unique database can facilitate researchers to investigate prostate cancer protein biomarkers in blood samples. In the real-world use of the spectrum library for biomarker detection, using a signature of 17 proteins, a clear distinction between the validation cohort's pre- and post-treatment groups was observed. Data are available via ProteomeXchange with identifier PXD028651.
Language	English
Publishing date	2021-11-08
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers13215580
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Article: Proteomic analysis identifies subgroups of patients with active systemic lupus erythematosus.

Su, Kevin Y C / Reynolds, John A / Reed, Rachel / Da Silva, Rachael / Kelsall, Janet / Baricevic-Jones, Ivona / Lee, David / Whetton, Anthony D / Geifman, Nophar / McHugh, Neil / Bruce, Ian N

Clinical proteomics

2023 Volume 20, Issue 1, Page(s) 29

Abstract: Objective: Systemic lupus erythematosus (SLE) is a clinically and biologically heterogenous autoimmune disease. We aimed to investigate the plasma proteome of patients with active SLE to identify novel subgroups, or endotypes, of patients.: Method: ... ...

Abstract	Objective: Systemic lupus erythematosus (SLE) is a clinically and biologically heterogenous autoimmune disease. We aimed to investigate the plasma proteome of patients with active SLE to identify novel subgroups, or endotypes, of patients. Method: Plasma was collected from patients with active SLE who were enrolled in the British Isles Lupus Assessment Group Biologics Registry (BILAG-BR). The plasma proteome was analysed using a data-independent acquisition method, Sequential Window Acquisition of All theoretical mass spectra mass spectrometry (SWATH-MS). Unsupervised, data-driven clustering algorithms were used to delineate groups of patients with a shared proteomic profile. Results: In 223 patients, six clusters were identified based on quantification of 581 proteins. Between the clusters, there were significant differences in age (p = 0.012) and ethnicity (p = 0.003). There was increased musculoskeletal disease activity in cluster 1 (C1), 19/27 (70.4%) (p = 0.002) and renal activity in cluster 6 (C6) 15/24 (62.5%) (p = 0.051). Anti-SSa/Ro was the only autoantibody that significantly differed between clusters (p = 0.017). C1 was associated with p21-activated kinases (PAK) and Phospholipase C (PLC) signalling. Within C1 there were two sub-clusters (C1A and C1B) defined by 49 proteins related to cytoskeletal protein binding. C2 and C6 demonstrated opposite Rho family GTPase and Rho GDI signalling. Three proteins (MZB1, SND1 and AGL) identified in C6 increased the classification of active renal disease although this did not reach statistical significance (p = 0.0617). Conclusions: Unsupervised proteomic analysis identifies clusters of patients with active SLE, that are associated with clinical and serological features, which may facilitate biomarker discovery. The observed proteomic heterogeneity further supports the need for a personalised approach to treatment in SLE.
Language	English
Publishing date	2023-07-29
Publishing country	England
Document type	Journal Article
ZDB-ID	2205154-5
ISSN	1542-6416
ISSN	1542-6416
DOI	10.1186/s12014-023-09420-1
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Article ; Online: Quantitative SWATH-based proteomic profiling of urine for the identification of endometrial cancer biomarkers in symptomatic women.

Njoku, Kelechi / Pierce, Andrew / Geary, Bethany / Campbell, Amy E / Kelsall, Janet / Reed, Rachel / Armit, Alexander / Da Sylva, Rachel / Zhang, Liqun / Agnew, Heather / Baricevic-Jones, Ivona / Chiasserini, Davide / Whetton, Anthony D / Crosbie, Emma J

British journal of cancer

2023 Volume 128, Issue 9, Page(s) 1723–1732

Abstract: Background: A non-invasive endometrial cancer detection tool that can accurately triage symptomatic women for definitive testing would improve patient care. Urine is an attractive biofluid for cancer detection due to its simplicity and ease of ... ...

Abstract	Background: A non-invasive endometrial cancer detection tool that can accurately triage symptomatic women for definitive testing would improve patient care. Urine is an attractive biofluid for cancer detection due to its simplicity and ease of collection. The aim of this study was to identify urine-based proteomic signatures that can discriminate endometrial cancer patients from symptomatic controls. Methods: This was a prospective case-control study of symptomatic post-menopausal women (50 cancers, 54 controls). Voided self-collected urine samples were processed for mass spectrometry and run using sequential window acquisition of all theoretical mass spectra (SWATH-MS). Machine learning techniques were used to identify important discriminatory proteins, which were subsequently combined in multi-marker panels using logistic regression. Results: The top discriminatory proteins individually showed moderate accuracy (AUC > 0.70) for endometrial cancer detection. However, algorithms combining the most discriminatory proteins performed well with AUCs > 0.90. The best performing diagnostic model was a 10-marker panel combining SPRR1B, CRNN, CALML3, TXN, FABP5, C1RL, MMP9, ECM1, S100A7 and CFI and predicted endometrial cancer with an AUC of 0.92 (0.96-0.97). Urine-based protein signatures showed good accuracy for the detection of early-stage cancers (AUC 0.92 (0.86-0.9)). Conclusion: A patient-friendly, urine-based test could offer a non-invasive endometrial cancer detection tool in symptomatic women. Validation in a larger independent cohort is warranted.
MeSH term(s)	Humans ; Female ; Biomarkers, Tumor ; Case-Control Studies ; Proteomics/methods ; Biomarkers ; Mass Spectrometry/methods ; Endometrial Neoplasms/diagnosis ; Fatty Acid-Binding Proteins ; Extracellular Matrix Proteins
Chemical Substances	Biomarkers, Tumor ; Biomarkers ; FABP5 protein, human ; Fatty Acid-Binding Proteins ; ECM1 protein, human ; Extracellular Matrix Proteins
Language	English
Publishing date	2023-02-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80075-2
ISSN	1532-1827 ; 0007-0920
ISSN (online)	1532-1827
ISSN	0007-0920
DOI	10.1038/s41416-022-02139-0
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Article ; Online: The role of microRNAs in the pathogenesis of MMPi-induced skin fibrodysplasia.

Tonge, Daniel P / Tugwood, Jonathan D / Kelsall, Janet / Gant, Timothy W

BMC genomics

2013 Volume 14, Page(s) 338

Abstract: Background: Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes involved in extracellular matrix (ECM) homeostasis. MMPs have been an attractive pharmacological target for a number of indications. However, development has been hampered ... ...

Abstract	Background: Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes involved in extracellular matrix (ECM) homeostasis. MMPs have been an attractive pharmacological target for a number of indications. However, development has been hampered by the propensity of compounds targeting these enzymes to cause connective-tissue pathologies. The broad-spectrum MMP-inhibitor (MMPi) AZM551248 has been shown to induce such effects in the dog. Histopathological changes were consistent with fibrodysplasia (FD), characterised by fibroblast proliferation and the deposition of collagen in the subcutaneous tissues. We conducted a time-course study administering 20mg/kg/day AZM551248 between 4 and 17 days. Cervical subcutaneous tissue and plasma were sampled during the time-course. miRNA expression profiles in subcutaneous skin specimens following the administration of AZM551248 were determined by high-throughput-sequencing. Results: An increasing number of miRNAs were differentially expressed compared with vehicle treated control animals as the study progressed. Several of these were members of the miR-200 family and were significantly attenuated in response to MMPi. As the severity of FD increased at the later time-points, other miRNAs associated with TGFβ synthesis and regulation of the acute inflammatory response were modulated. Evidence indicative of epithelial to mesenchymal transition was present at all study time points. Receiver operator curve (ROC) analysis revealed that miR-21 expression in the cervical subcutaneous tissue was a sensitive and specific biomarker of FD incidence. Conclusions: Our data reveal significant perturbations in canine skin miRNA expression in response to MMPi administration. Furthermore, we have identified dysregulated miRNAs that are associated with processes relevant to the key histopathological events of MMPi-induced FD.
MeSH term(s)	Animals ; Biomarkers/blood ; Collagen Type III/blood ; Connective Tissue Diseases/blood ; Connective Tissue Diseases/chemically induced ; Connective Tissue Diseases/genetics ; Connective Tissue Diseases/pathology ; Disease Progression ; Dogs ; Gene Expression Profiling ; Matrix Metalloproteinase Inhibitors/adverse effects ; Matrix Metalloproteinases/metabolism ; MicroRNAs/genetics ; Piperazines/adverse effects ; Safety ; Skin/pathology ; Subcutaneous Tissue/drug effects ; Subcutaneous Tissue/metabolism ; Subcutaneous Tissue/pathology ; Time Factors
Chemical Substances	AZM551248 ; Biomarkers ; Collagen Type III ; Matrix Metalloproteinase Inhibitors ; MicroRNAs ; Piperazines ; Matrix Metalloproteinases (EC 3.4.24.-)
Language	English
Publishing date	2013-05-20
Publishing country	England
Document type	Journal Article
ISSN	1471-2164
ISSN (online)	1471-2164
DOI	10.1186/1471-2164-14-338
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Article ; Online: The use of missing values in proteomic data-independent acquisition mass spectrometry to enable disease activity discrimination.

McGurk, Kathryn A / Dagliati, Arianna / Chiasserini, Davide / Lee, Dave / Plant, Darren / Baricevic-Jones, Ivona / Kelsall, Janet / Eineman, Rachael / Reed, Rachel / Geary, Bethany / Unwin, Richard D / Nicolaou, Anna / Keavney, Bernard D / Barton, Anne / Whetton, Anthony D / Geifman, Nophar

Bioinformatics (Oxford, England)

2019 Volume 36, Issue 7, Page(s) 2217–2223

Abstract: Motivation: Data-independent acquisition mass spectrometry allows for comprehensive peptide detection and relative quantification than standard data-dependent approaches. While less prone to missing values, these still exist. Current approaches for ... ...

Abstract	Motivation: Data-independent acquisition mass spectrometry allows for comprehensive peptide detection and relative quantification than standard data-dependent approaches. While less prone to missing values, these still exist. Current approaches for handling the so-called missingness have challenges. We hypothesized that non-random missingness is a useful biological measure and demonstrate the importance of analysing missingness for proteomic discovery within a longitudinal study of disease activity. Results: The magnitude of missingness did not correlate with mean peptide concentration. The magnitude of missingness for each protein strongly correlated between collection time points (baseline, 3 months, 6 months; R = 0.95-0.97, confidence interval = 0.94-0.97) indicating little time-dependent effect. This allowed for the identification of proteins with outlier levels of missingness that differentiate between the patient groups characterized by different patterns of disease activity. The association of these proteins with disease activity was confirmed by machine learning techniques. Our novel approach complements analyses on complete observations and other missing value strategies in biomarker prediction of disease activity. Supplementary information: Supplementary data are available at Bioinformatics online.
MeSH term(s)	Humans ; Longitudinal Studies ; Mass Spectrometry ; Proteomics
Language	English
Publishing date	2019-11-27
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1422668-6
ISSN	1367-4811 ; 1367-4803
ISSN (online)	1367-4811
ISSN	1367-4803
DOI	10.1093/bioinformatics/btz898
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Article ; Online: Fibrodysplasia induced in dog skin by a matrix metalloproteinase (MMP) inhibitor--a mechanistic analysis.

Tugwood, Jonathan D / Kelsall, Janet / Coverley, Lucy C / Westwood, F Russell / Haque, Kemal / Huby, Russell D J

Toxicological sciences : an official journal of the Society of Toxicology

2012 Volume 127, Issue 1, Page(s) 236–245

Abstract: Matrix metalloproteinase (MMP) inhibitors, candidate therapeutic agents for a number of diseases, are known to be associated with acute fibrosis-type adverse effects in a number of species, including humans. The broad-spectrum MMP inhibitor, AZM551248, ... ...

Abstract	Matrix metalloproteinase (MMP) inhibitors, candidate therapeutic agents for a number of diseases, are known to be associated with acute fibrosis-type adverse effects in a number of species, including humans. The broad-spectrum MMP inhibitor, AZM551248, has previously been shown to cause these effects in the dog. Changes were characterized by the abnormal and extensive proliferation of fibroblasts and the deposition of collagen particularly in the subcutaneous connective tissues (subcutis) and were termed fibrodysplasia (FD). We performed a time-course study in dogs using AZM551248 and sampled skin, subcutis, and plasma before and during the development of FD. Detailed histopathological analysis and global gene expression profiling were performed on the subcutaneous tissues. The gene expression analysis of the subcutis indicated that extracellular matrix (ECM) remodeling was initiated asymptomatically at or before the earliest time point, day 4, and this was associated with dysregulation of expression of a number of MMPs and proteolytic enzymes. At later time points, the FD became progressively more extensive and severe, and this was associated with gene expression changes characteristic of tissue fibrosis, for example those associated with procollagen synthesis and processing. We postulate that AZM551248 inhibition of MMP action within the subcutis modulates the activity of several transcription factors and this in turn upregulates expression of specific proteases which initiate ECM remodeling. Persistent MMP inhibition results in the progression of ECM remodeling, culminating in collagen deposition and overt fibrosis. Our data indicate that inhibition of MMPs 1, 2, 3, and 9 is a key early event in AZM551248-induced FD in dog subcutis.
MeSH term(s)	Animals ; Collagen/metabolism ; Connective Tissue/drug effects ; Connective Tissue/pathology ; Disease Models, Animal ; Dogs ; Extracellular Matrix/drug effects ; Extracellular Matrix/metabolism ; Female ; Fibrosis/chemically induced ; Fibrosis/metabolism ; Fibrosis/pathology ; Gene Expression/drug effects ; Gene Expression Profiling ; Genome-Wide Association Study ; Matrix Metalloproteinase Inhibitors ; Matrix Metalloproteinases/genetics ; Matrix Metalloproteinases/metabolism ; Oligonucleotide Array Sequence Analysis ; Piperazines/toxicity ; Protease Inhibitors/toxicity ; Real-Time Polymerase Chain Reaction ; Skin/drug effects ; Skin/pathology
Chemical Substances	AZM551248 ; Matrix Metalloproteinase Inhibitors ; Piperazines ; Protease Inhibitors ; Collagen (9007-34-5) ; Matrix Metalloproteinases (EC 3.4.24.-)
Language	English
Publishing date	2012-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	1420885-4
ISSN	1096-0929 ; 1096-6080
ISSN (online)	1096-0929
ISSN	1096-6080
DOI	10.1093/toxsci/kfs075
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Article ; Online: Absolute Measurement of Cardiac Injury-Induced microRNAs in Biofluids across Multiple Test Sites.

Toxicological sciences : an official journal of the Society of Toxicology

2016 Volume 154, Issue 1, Page(s) 115–125

Abstract: Extracellular microRNAs (miRNAs) represent a promising new source of toxicity biomarkers that are sensitive indicators of site of tissue injury. In order to establish reliable approaches for use in biomarker validation studies, the HESI technical ... ...

Abstract	Extracellular microRNAs (miRNAs) represent a promising new source of toxicity biomarkers that are sensitive indicators of site of tissue injury. In order to establish reliable approaches for use in biomarker validation studies, the HESI technical committee on genomics initiated a multi-site study to assess sources of variance associated with quantitating levels of cardiac injury induced miRNAs in biofluids using RT-qPCR. Samples were generated at a central site using a model of acute cardiac injury induced in male Wistar rats by 0.5 mg/kg isoproterenol. Biofluid samples were sent to 11 sites for measurement of 3 cardiac enriched miRNAs (miR-1-3p, miR-208a-3p, and miR-499-5p) and 1 miRNA abundant in blood (miR-16-5p) or urine (miR-192-5p) by absolute quantification using calibration curves of synthetic miRNAs. The samples included serum and plasma prepared from blood collected at 4 h, urine collected from 6 to 24 h, and plasma prepared from blood collected at 24 h post subcutaneous injection. A 3 parameter logistic model was utilized to fit the calibration curve data and estimate levels of miRNAs in biofluid samples by inverse prediction. Most sites observed increased circulating levels of miR-1-3p and miR-208a-3p at 4 and 24 h after isoproterenol treatment, with no difference seen between serum and plasma. The biological differences in miRNA levels and sample type dominated as sources of variance, along with outlying performance by a few sites. The standard protocol established in this study was successfully implemented across multiple sites and provides a benchmark method for further improvements in quantitative assays for circulating miRNAs.
Language	English
Publishing date	2016-11
Publishing country	United States
Document type	Journal Article
ZDB-ID	1420885-4
ISSN	1096-0929 ; 1096-6080
ISSN (online)	1096-0929
ISSN	1096-6080
DOI	10.1093/toxsci/kfw143
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