Active Ratio Test (ART) as a Novel Diagnostic for Ovarian Cancer

Background: Despite substantial effort, there remains a lack of biomarker-based, clinically relevant testing for the accurate, non-invasive diagnostic or prognostic profiling of epithelial ovarian cancers (EOC). Our previous work demonstrated that whilst the inflammatory marker C-X-C motif chemokine ligand 10 (CXCL10) has prognostic relevance in ovarian cancer, its use is complicated by the presence of multiple, N-terminally modified variants, mediated by several enzymes including Dipeptidyl Peptidase 4 (DPP4). Methods: In this study, we provide the first evidence for the “Active Ratio Test” (ART) as a novel method to measure biologically relevant CXCL10 proteoforms in clinical samples. Results: In a cohort of 275 patients, ART accurately differentiated patients with malignant EOCs from those with benign gynaecological conditions (AUC 0.8617) and significantly out-performed CA125 alone. Moreover, ART combined with the measurement of CA125 and DPP4 significantly increased prognostic performance (AUC 0.9511; sensitivity 90.0%; specificity 91.7%; Cohen’s d > 1) for EOC detection. Conclusion: Our data demonstrate that ART provides a useful method to accurately discriminate between patients with benign versus malignant EOC, and highlights their relevance to ovarian cancer diagnosis. This marker combination may also be applicable in broader screening applications, to identify or discriminate benign from malignant disease in asymptomatic women.

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Diagnostic potential for a serum miRNA neural network for detection of ovarian cancer

eLife ◽

10.7554/elife.28932 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 38

Author(s):

Kevin M Elias ◽

Wojciech Fendler ◽

Konrad Stawiski ◽

Stephen J Fiascone ◽

Allison F Vitonis ◽

...

Keyword(s):

Neural Network ◽

Ovarian Cancer ◽

Predictive Value ◽

Clinical Samples ◽

Small Rna Sequencing ◽

Serum Samples ◽

Non Invasive ◽

Metastatic Lesions ◽

Diagnostic Potential ◽

The Neural Network

Recent studies posit a role for non-coding RNAs in epithelial ovarian cancer (EOC). Combining small RNA sequencing from 179 human serum samples with a neural network analysis produced a miRNA algorithm for diagnosis of EOC (AUC 0.90; 95% CI: 0.81–0.99). The model significantly outperformed CA125 and functioned well regardless of patient age, histology, or stage. Among 454 patients with various diagnoses, the miRNA neural network had 100% specificity for ovarian cancer. After using 325 samples to adapt the neural network to qPCR measurements, the model was validated using 51 independent clinical samples, with a positive predictive value of 91.3% (95% CI: 73.3–97.6%) and negative predictive value of 78.6% (95% CI: 64.2–88.2%). Finally, biologic relevance was tested using in situ hybridization on 30 pre-metastatic lesions, showing intratumoral concentration of relevant miRNAs. These data suggest circulating miRNAs have potential to develop a non-invasive diagnostic test for ovarian cancer.

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Bee Markers: A Novel Method for Non-Invasive Short Term Marking of Bats

Acta Chiropterologica ◽

10.3161/15081109acc2019.21.2.020 ◽

2020 ◽

Vol 21 (2) ◽

pp. 465 ◽

Cited By ~ 1

Author(s):

Lucinda Kirkpatrick ◽

Grzegorz Apoznański ◽

Luc De Bruyn ◽

Ralf Gyselings ◽

Tomasz Kokurewicz

Keyword(s):

Short Term ◽

Non Invasive ◽

Novel Method

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USP48 Sustains Chemoresistance and Metastasis in Ovarian Cancer

Current Cancer Drug Targets ◽

10.2174/1568009620666200503045400 ◽

2020 ◽

Vol 20 (9) ◽

pp. 689-699

Author(s):

Xuemeng Lei ◽

Xukun Li ◽

Hongyan Chen ◽

Zhihua Liu

Keyword(s):

Ovarian Cancer ◽

Cancer Patients ◽

Migration And Invasion ◽

Clinical Samples ◽

Deubiquitinating Enzymes ◽

Potential Therapeutic Target ◽

Kaplan Meier ◽

Specific Protease ◽

Ubiquitin Specific Protease

Background: Ubiquitin specific protease 48 (USP48) is a member of the deubiquitinating enzymes (DUBs) family. However, the function of USP48 in ovarian cancer remains unclear. Objective: The present study reveals that USP48 knockdown could significantly inhibit cell migration and invasion in ES2, 3AO and A2780 cells, without affecting cell proliferation. Methods: After carboplatin (CBP) treatment, the USP48 ablation increases the apoptosis rate, and the cleaved PARP and cleaved caspase 3 expression levels in ES2, 3AO and A2780 cells. The subcutaneous tumor and intraperitoneally injected experiments demonstrated that the USP48 knockdown significantly increases responsiveness to CBP, and alleviates the metastasis in vivo. Meanwhile, USP48 deficiency results in the improved survival of mice. Results: Finally, the analysis of clinical samples and the TCGA and Kaplan-Meier Plot database revealed that the high expression of USP48 in ovarian cancer patients is associated with poor survival and resistance to CBP therapy. Conclusion: In summary, USP48 may be a potential therapeutic target for ovarian cancer patients.

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CC Chemokine Ligand 7 Derived from Cancer-Stimulated Macrophages Promotes Ovarian Cancer Cell Invasion

Cancers ◽

10.3390/cancers13112745 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2745

Author(s):

Miran Jeong ◽

Yi-Yue Wang ◽

Ju-Yeon Choi ◽

Myong-Cheol Lim ◽

Jung-Hye Choi

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Cancer Cell ◽

Cell Invasion ◽

Ovarian Cancer Cell ◽

Ovarian Cancer Cells ◽

Human Ovarian Cancer ◽

Cancer Cell Invasion ◽

Cc Chemokine ◽

Chemokine Ligand

In the tumor microenvironment, macrophages have been suggested to be stimulated by tumor cells, becoming tumor-associated macrophages that promote cancer development and progression. We examined the effect of these macrophages on human ovarian cancer cell invasion and found that conditioned medium of macrophages stimulated by ovarian cancer cells (OC-MQs) significantly increased cell invasion. CC chemokine ligand 7 (CCL7) expression and production were significantly higher in OC-MQs than in the control macrophages. Peritoneal macrophages from patients with ovarian cancer showed higher CCL7 expression levels than those from healthy controls. Inhibition of CCL7 using siRNA and neutralizing antibodies reduced the OC-MQ-CM-induced ovarian cancer cell invasion. CC chemokine receptor 3 (CCR3) was highly expressed in human ovarian cancer cells, and a specific inhibitor of this receptor reduced the OC-MQ-CM-induced invasion. Specific signaling and transcription factors were associated with enhanced CCL7 expression in OC-MQs. CCL7-induced invasion required the expression of matrix metalloproteinase 9 via activation of extracellular signal-related kinase signaling in human ovarian cancer cells. These data suggest that tumor-associated macrophages can affect human ovarian cancer metastasis via the CCL7/CCR3 axis.

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BARD1 Autoantibody Blood Test for Early Detection of Ovarian Cancer

Genes ◽

10.3390/genes12070969 ◽

2021 ◽

Vol 12 (7) ◽

pp. 969

Author(s):

Maxim Pilyugin ◽

Magda Ratasjka ◽

Maciej Stukan ◽

Nicole Concin ◽

Robert Zeillinger ◽

...

Keyword(s):

Ovarian Cancer ◽

Early Detection ◽

Blood Test ◽

Menopausal Status ◽

Clinical Samples ◽

Average Risk ◽

Healthy Controls ◽

Cancer Antigen 125 ◽

Cancer Syndrome ◽

Ovarian Cancer Screening

Background: Ovarian cancer (OC) is the most lethal gynaecological cancer. It is often diagnosed at an advanced stage with poor chances for successful treatment. An accurate blood test for the early detection of OC could reduce the mortality of this disease. Methods: Autoantibody reactivity to 20 epitopes of BARD1 and concentration of cancer antigen 125 (CA125) were assessed in 480 serum samples of OC patients and healthy controls. Autoantibody reactivity and CA125 were also tested for 261 plasma samples of OC with or without mutations in BRCA1/2, BARD1, or other predisposing genes, and healthy controls. Lasso statistic regression was applied to measurements to develop an algorithm for discrimination between OC and controls. Findings and interpretation: Measurement of autoantibody binding to a number of BARD1 epitopes combined with CA125 could distinguish OC from healthy controls with high accuracy. This BARD1-CA125 test was more accurate than measurements of BARD1 autoantibody or CA125 alone for all OC stages and menopausal status. A BARD1-CA125-based test is expected to work equally well for average-risk women and high-risk women with hereditary breast and ovarian cancer syndrome (HBOC). Although these results are promising, further data on well-characterised clinical samples shall be used to confirm the potential of the BARD1-CA125 test for ovarian cancer screening.

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Immunomagnetic sequential ultrafiltration (iSUF) platform for enrichment and purification of extracellular vesicles from biofluids

Scientific Reports ◽

10.1038/s41598-021-86910-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jingjing Zhang ◽

Luong T. H. Nguyen ◽

Richard Hickey ◽

Nicole Walters ◽

Xinyu Wang ◽

...

Keyword(s):

Extracellular Vesicles ◽

Culture Media ◽

Metastatic Breast ◽

Clinical Samples ◽

Clinical Use ◽

Immunomagnetic Beads ◽

Liquid Biopsies ◽

Cell Culture Media ◽

Non Invasive ◽

Healthy Donors

AbstractExtracellular vesicles (EVs) derived from tumor cells have the potential to provide a much-needed source of non-invasive molecular biomarkers for liquid biopsies. However, current methods for EV isolation have limited specificity towards tumor-derived EVs that limit their clinical use. Here, we present an approach called immunomagnetic sequential ultrafiltration (iSUF) that consists of sequential stages of purification and enrichment of EVs in approximately 2 h. In iSUF, EVs present in different volumes of biofluids (0.5–100 mL) can be significantly enriched (up to 1000 times), with up to 99% removal of contaminating proteins (e.g., albumin). The EV recovery rate by iSUF for cell culture media (CCM), serum, and urine corresponded to 98.0% ± 3.6%, 96.0% ± 2.0% and 94.0% ± 1.9%, respectively (p > 0.05). The final step of iSUF enables the separation of tumor-specific EVs by incorporating immunomagnetic beads to target EV subpopulations. Serum from a cohort of clinical samples from metastatic breast cancer (BC) patients and healthy donors were processed by the iSUF platform and the isolated EVs from patients showed significantly higher expression levels of BC biomarkers (i.e., HER2, CD24, and miR21).

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Oncogenic Role of miR-200c-3p in High-Grade Serous Ovarian Cancer Progression via Targeting the 3′-Untranslated Region of DLC1

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18115741 ◽

2021 ◽

Vol 18 (11) ◽

pp. 5741

Author(s):

Sheril June Ankasha ◽

Mohamad Nasir Shafiee ◽

Norhazlina Abdul Wahab ◽

Raja Affendi Raja Ali ◽

Norfilza Mohd Mokhtar

Keyword(s):

Ovarian Cancer ◽

Cancer Progression ◽

Untranslated Region ◽

Luciferase Reporter ◽

Clinical Samples ◽

Binding Motif ◽

Skov3 Cell ◽

High Grade ◽

Serous Ovarian Cancer ◽

Dlc1 Expression

High-grade serous ovarian cancer (HGSC) is the most common ovarian cancer with highly metastatic properties. A small non-coding RNA, microRNA (miRNA) was discovered to be a major regulator in many types of cancers through binding at the 3′-untranslated region (3′UTR), leading to degradation of the mRNA. In this study, we sought to investigate the underlying mechanisms involved in the dysregulation of miR-200c-3p in HGSC progression and metastasis. We identified the upregulation of miR-200c-3p expression in different stages of HGSC clinical samples and the downregulation of the tumor suppressor gene, Deleted in Liver Cancer 1 (DLC1), expression. Over expression of miR-200c-3p in HGSC cell lines downregulated DLC1 but upregulated the epithelial marker, E-cadherin (CDH1). Based on in silico analysis, two putative binding sites were found within the 3′UTR of DLC1, and we confirmed the direct binding of miR-200c-3p to the target binding motif at position 1488–1495 bp of 3′UTR of DLC1 by luciferase reporter assay in a SKOV3 cell line co-transfected with vectors and miR-200c-3p mimic. These data showed that miR-200c-3p regulated the progression of HGSC by regulating DLC1 expression post-transcription and can be considered as a promising target for therapeutic purposes.

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A Review of Murine Cytomegalovirus as a Model for Human Cytomegalovirus Disease—Do Mice Lie?

International Journal of Molecular Sciences ◽

10.3390/ijms22010214 ◽

2020 ◽

Vol 22 (1) ◽

pp. 214

Author(s):

Michelle A. Fisher ◽

Megan L. Lloyd

Keyword(s):

Human Cytomegalovirus ◽

Murine Cytomegalovirus ◽

Clinical Samples ◽

Mouse Strains ◽

Cytomegalovirus Disease ◽

Wild Mice ◽

Congenital Cytomegalovirus ◽

Non Invasive ◽

Species Specific ◽

Disseminated Disease

Since murine cytomegalovirus (MCMV) was first described in 1954, it has been used to model human cytomegalovirus (HCMV) diseases. MCMV is a natural pathogen of mice that is present in wild mice populations and has been associated with diseases such as myocarditis. The species-specific nature of HCMV restricts most research to cell culture-based studies or to the investigation of non-invasive clinical samples, which may not be ideal for the study of disseminated disease. Initial MCMV research used a salivary gland-propagated virus administered via different routes of inoculation into a variety of mouse strains. This revealed that the genetic background of the laboratory mice affected the severity of disease and altered the extent of subsequent pathology. The advent of genetically modified mice and viruses has allowed new aspects of disease to be modeled and the opportunistic nature of HCMV infection to be confirmed. This review describes the different ways that MCMV has been used to model HCMV diseases and explores the continuing difficulty faced by researchers attempting to model HCMV congenital cytomegalovirus disease using the mouse model.

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Potential clinical applications of circulating cell-free DNA in ovarian cancer patients

Expert Reviews in Molecular Medicine ◽

10.1017/erm.2018.5 ◽

2018 ◽

Vol 20 ◽

Cited By ~ 4

Author(s):

Ana Barbosa ◽

Ana Peixoto ◽

Pedro Pinto ◽

Manuela Pinheiro ◽

Manuel R. Teixeira

Keyword(s):

Ovarian Cancer ◽

Cancer Patients ◽

Liquid Biopsy ◽

Clinical Applications ◽

Epigenetic Alterations ◽

Cell Free Dna ◽

Non Invasive ◽

Free Dna ◽

Potential Use ◽

Circulating Cell Free Dna

AbstractCirculating cell-free DNA (cfDNA) consists of small fragments of DNA that circulate freely in the bloodstream. In cancer patients, a fraction of cfDNA is derived from tumour cells, therefore containing the same genetic and epigenetic alterations, and is termed circulating cell-free tumour DNA. The potential use of cfDNA, the so-called ‘liquid biopsy’, as a non-invasive cancer biomarker has recently received a lot of attention. The present review will focus on studies concerning the potential clinical applications of cfDNA in ovarian cancer patients.

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