Publications
18 results found
Merali N, Chouari T, Terroire J, et al., 2023, Bile microbiome signatures associated with pancreatic ductal adenocarcinoma compared to benign disease: a UK pilot study, International Journal of Molecular Sciences, Vol: 24, ISSN: 1422-0067
Pancreatic ductal adenocarcinoma (PDAC) has a very poor survival. The intra-tumoural microbiome can influence pancreatic tumourigenesis and chemoresistance and, therefore, patient survival. The role played by bile microbiota in PDAC is unknown. We aimed to define bile microbiome signatures that can effectively distinguish malignant from benign tumours in patients presenting with obstructive jaundice caused by benign and malignant pancreaticobiliary disease. Prospective bile samples were obtained from 31 patients who underwent either Endoscopic Retrograde Cholangiopancreatography (ERCP) or Percutaneous Transhepatic Cholangiogram (PTC). Variable regions (V3-V4) of the 16S rRNA genes of microorganisms present in the samples were amplified by Polymerase Chain Reaction (PCR) and sequenced. The cohort consisted of 12 PDAC, 10 choledocholithiasis, seven gallstone pancreatitis and two primary sclerosing cholangitis patients. Using the 16S rRNA method, we identified a total of 135 genera from 29 individuals (12 PDAC and 17 benign). The bile microbial beta diversity significantly differed between patients with PDAC vs. benign disease (Permanova p = 0.0173). The separation of PDAC from benign samples is clearly seen through unsupervised clustering of Aitchison distance. We found three genera to be of significantly lower abundance among PDAC samples vs. benign, adjusting for false discovery rate (FDR). These were Escherichia (FDR = 0.002) and two unclassified genera, one from Proteobacteria (FDR = 0.002) and one from Enterobacteriaceae (FDR = 0.011). In the same samples, the genus Streptococcus (FDR = 0.033) was found to be of increased abundance in the PDAC group. We show that patients with obstructive jaundice caused by PDAC have an altered microbiome composition in the bile compared to those with benign disease. These bile-based microbes could be developed into potential diagnostic and prognostic biomarkers for PDAC and warrant further investigation.
Patel BY, Bhome R, Liu DSK, et al., 2023, Cancer cell-derived extracellular vesicles activate hepatic stellate cells in colorectal cancer, EXPERT REVIEW OF MOLECULAR DIAGNOSTICS, ISSN: 1473-7159
Yin T, Xu L, Gil B, et al., 2023, Graphene sensor arrays for rapid and accurate detection of pancreatic cancer exosomes in patients' blood plasma samples, ACS Nano, Vol: 17, Pages: 14619-14631, ISSN: 1936-0851
Biosensors based on graphene field effect transistors (GFETs) have the potential to enable the development of point-of-care diagnostic tools for early stage disease detection. However, issues with reproducibility and manufacturing yields of graphene sensors, but also with Debye screening and unwanted detection of nonspecific species, have prevented the wider clinical use of graphene technology. Here, we demonstrate that our wafer-scalable GFETs array platform enables meaningful clinical results. As a case study of high clinical relevance, we demonstrate an accurate and robust portable GFET array biosensor platform for the detection of pancreatic ductal adenocarcinoma (PDAC) in patients’ plasma through specific exosomes (GPC-1 expression) within 45 min. In order to facilitate reproducible detection in blood plasma, we optimized the analytical performance of GFET biosensors via the application of an internal control channel and the development of an optimized test protocol. Based on samples from 18 PDAC patients and 8 healthy controls, the GFET biosensor arrays could accurately discriminate between the two groups while being able to detect early cancer stages including stages 1 and 2. Furthermore, we confirmed the higher expression of GPC-1 and found that the concentration in PDAC plasma was on average more than 1 order of magnitude higher than in healthy samples. We found that these characteristics of GPC-1 cancerous exosomes are responsible for an increase in the number of target exosomes on the surface of graphene, leading to an improved signal response of the GFET biosensors. This GFET biosensor platform holds great promise for the development of an accurate tool for the rapid diagnosis of pancreatic cancer.
Liu DSK, Frampton AE, 2022, Plasma extracellular vesicles contain unannotated small RNA clusters suitable as biomarkers for detecting early hepatocellular carcinoma, GUT, Vol: 71, Pages: 1935-1936, ISSN: 0017-5749
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- Citations: 2
Liu D, Yang QZC, Asim M, et al., 2022, The clinical significance of transfer RNAs present in extracellular vesicles, International Journal of Molecular Sciences, Vol: 23, ISSN: 1422-0067
Extracellular vesicles (EVs) are important for intercellular signalling in multi-cellular organ-isms. However, the role of mature transfer RNAs (tRNAs) and tRNA fragments in EVs has yet to be characterised. This systematic review aimed to identify up-to-date literature on tRNAs pre-sent within human EVs and explores their potential clinical significance in health and disease. A comprehensive and systematic literature search was performed, and the study was conducted in accordance with PRISMA guidelines. Electronic databases MEDLINE and EMBASE were searched up until 1st January 2022. From 685 papers, 60 studies were identified for analysis. The majority of papers reviewed focussed on the role of EV tRNAs in cancers (31.7%), with numerous other conditions represented. Blood and cell lines were the most common EV sources, representing 85.9% of protocols used. EV isolation methods included the most known methods, precipitation being the most common (49.3%). The proportion of EV tRNAs was highly variable, ranging be-tween 0.04% to >95% depending on tissue source. EV tRNAs are present in a multitude of sources and show promise as disease markers in breast cancer, gastrointestinal cancers, and other diseases. EV tRNA research is an emerging field, with increasing numbers of papers highlighting novel methodologies for tRNA and tRNA fragment discovery.
Lythgoe M, Adriani M, Stebbing J, et al., 2021, 543P Neoadjuvant MRx0518 treatment is associated with significant gene and metagene signature changes in solid tumours, Annals of Oncology, Vol: 32, Pages: S607-S607, ISSN: 0923-7534
BackgroundMRx0518 is an oral live biotherapeutic with potent immunostimulatory activity and anti-tumorigenic efficacy in murine models of lung (LLC1), kidney (Renca) and breast (EMT6) cancer. Previous reports have demonstrated a favourable safety profile in neoadjuvant and metastatic clinical settings, with emerging evidence of immune modulation. We performed a comprehensive analysis of the gene and metagene signature in cancer patients treated with MRx0518 monotherapy.MethodsTreatment-naïve patients with a histologically confirmed diagnosis of cancer scheduled for surgical resection were recruited from April 2019 to February 2020. Patients received 1 capsule of MRx0518 (1x1010 to 1x1011CFU) twice daily from inclusion until the day preceding surgery. Safety and tolerability (CTCAE v4.03) were the primary endpoints of this study. Comprehensive biomarker analysis was also performed in paired pre-treatment (diagnostic biopsy) and post-treatment (surgical specimen) samples using the NanoString IO 360 panel to explore gene and metagene signatures.Results31 samples were collected across tumour groups including breast (n=13) prostate (n=8), uterine (n=6), melanoma (n=2) and bladder (n=2). Differential expression analysis showed significant (p<0.05) increases in genes and metagenes associated with anti-tumour activity, including antigen presentation (AXL & CXCL12), innate immune processes (CHUK, RELA, PPARG & HRAS), interferon response (IFNGR1 & IFNGR2), Th1 cells and CD8+ cells following MRx0518 therapy, echoing preclinical findings. Novel changes, not previously detected in murine models, involving endothelial, mast cells, inflammatory myeloid and inflammatory chemokines were also observed, suggesting MRx0518 may have additional in vivo anti-tumorigenic effects. These changes were more pronounced in the breast cancer cohort.ConclusionsThis analysis, mirrors previous immunostimulatory activity and anti-tumorigenic efficacy observations seen in pre-clini
Lythgoe MP, Liu DSK, Annels NE, et al., 2021, Gene of the month: lymphocyte-activation gene 3 (LAG-3), JOURNAL OF CLINICAL PATHOLOGY, Vol: 74, Pages: 543-547, ISSN: 0021-9746
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- Citations: 28
Jimenez B, Abellona MRU, Drymousis P, et al., 2021, Neuroendocrine neoplasms: identification of novel metabolic circuits of potential diagnostic utility, Cancers, Vol: 13, ISSN: 2072-6694
The incidence of neuroendocrine neoplasms (NEN) is increasing, but established biomarkers have poor diagnostic and prognostic accuracy. Here, we aim to define the systemic metabolic consequences of NEN and to establish the diagnostic utility of proton nuclear magnetic resonance spectroscopy (1H-NMR) for NEN in a prospective cohort of patients through a single-centre, prospective controlled observational study. Urine samples of 34 treatment-naïve NEN patients (median age: 59.3 years, range: 36–85): 18 had pancreatic (Pan) NEN, of which seven were functioning; 16 had small bowel (SB) NEN; 20 age- and sex-matched healthy control individuals were analysed using a 600 MHz Bruker 1H-NMR spectrometer. Orthogonal partial-least-squares-discriminant analysis models were able to discriminate both PanNEN and SBNEN patients from healthy control (Healthy vs. PanNEN: AUC = 0.90, Healthy vs. SBNEN: AUC = 0.90). Secondary metabolites of tryptophan, such as trigonelline and a niacin-related metabolite were also identified to be universally decreased in NEN patients, while upstream metabolites, such as kynurenine, were elevated in SBNEN. Hippurate, a gut-derived metabolite, was reduced in all patients, whereas other gut microbial co-metabolites, trimethylamine-N-oxide, 4-hydroxyphenylacetate and phenylacetylglutamine, were elevated in those with SBNEN. These findings suggest the existence of a new systems-based neuroendocrine circuit, regulated in part by cancer metabolism, neuroendocrine signalling molecules and gut microbial co-metabolism. Metabonomic profiling of NEN has diagnostic potential and could be used for discovering biomarkers for these tumours. These preliminary data require confirmation in a larger cohort.
Limb C, Liu D, Veno M, et al., 2020, The role of circular RNAs in pancreatic ductal adenocarcinoma and biliary-tract cancers, Cancers, Vol: 12, ISSN: 2072-6694
Pancreatic Ductal Adenocarcinoma (PDAC) and biliary-tract cancers (BTC) often present at a late stage, and consequently patients have poor survival-outcomes. Circular RNAs (circRNAs) are non-coding RNA molecules whose role in tumourigenesis has recently been realised. They are stable, conserved and abundant, with tissue-specific expression profiles. Therefore, significant interest has arisen in their use as potential biomarkers for PDAC and BTC. High-throughput methods and more advanced bioinformatic techniques have enabled better profiling and progressed our understanding of how circRNAs may function in the competing endogenous RNA (ceRNA) network to influence the transcriptome in these cancers. Therefore, the aim of this systematic review was to describe the roles of circRNAs in PDAC and BTC, their potential as biomarkers, and their function in the wider ceRNA network in regulating microRNAs and the transcriptome. Medline, Embase, Scopus and PubMed were systematically reviewed to identify all the studies addressing circRNAs in PDAC and BTC. A total of 32 articles were included: 22 considering PDAC, 7 for Cholangiocarcinoma (CCA) and 3 for Gallbladder Cancer (GBC). There were no studies investigating Ampullary Cancer. Dysregulated circRNA expression was associated with features of malignancy in vitro, in vivo, and ex vivo. Overall, there have been very few PDAC and BTC tissues profiled for circRNA signatures. Therefore, whilst the current studies have demonstrated some of their functions in these cancers, further work is required to elucidate their potential role as cancer biomarkers in tissue, biofluids and biopsies.
Randazzo O, Papini F, Mantini G, et al., 2020, “Open Sesame?”: biomarker status of the human equilibrative nucleoside transporter-1 and molecular mechanisms influencing its expression and activity in the uptake and cytotoxicity of gemcitabine in pancreatic cancer, Cancers, Vol: 12, ISSN: 2072-6694
Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive tumor characterized by early invasiveness, rapid progression and resistance to treatment. Gemcitabine has been for more than twenty years the main therapy for PDAC both in the palliative and adjuvant setting. After the introduction of FOLFIRINOX as upfront treatment for metastatic disease, gemcitabine is still commonly used in combination with nab-paclitaxel as an alternative first-line regimen, as well as a monotherapy in elderly patients unfit for combination chemotherapy. As a hydrophilic nucleoside analogue, gemcitabine requires nucleoside transporters to permeate the plasma membrane, and a major role in the uptake of this drug is played by human equilibrative nucleoside transporter 1 (hENT-1). Several studies have proposed hENT-1 as a biomarker for gemcitabine efficacy in PDAC. A recent comprehensive multimodal analysis of hENT-1 status evaluated its predictive role by both immunohistochemistry (with five different antibodies), and quantitative-PCR, supporting the use of the 10D7G2 antibody. High hENT-1 levels observed with this antibody were associated with prolonged disease-free and overall-survival in patients receiving gemcitabine adjuvant chemotherapy. We discuss this analysis and lists molecular factors influencing hENT-1. Improved knowledge on these factors should help in the identification of subgroups of patients who may benefit from specific therapies and overcome the limitations of traditional biomarker studies.
Liu D, Upton F, Rees E, et al., 2020, Size exclusion chromatography as a technique for the investigation of novel extracellular vesicles in cancer, Cancers, Vol: 12, ISSN: 2072-6694
Abstract: (1) Background: Cancer cells release extracellular vesicles that are a rich target for biomarker discovery and provide a promising mechanism for liquid biopsy. SEC is an increasingly popular technique which has been rediscovered for the purposes of EV isolation and purification from diverse biofluids. (2) Methods: A review was undertaken to identify all papers which described size exclusion as their primary EV isolation method in cancer research. (3) Results: 37 papers were identified and discussed which showcases the breadth of applications that EVs can be utilised, from proteomics, to RNA, and through to functionality. A range of different methods are highlighted, with Sepharose-based techniques predominating. (4) Conclusions: EVs isolated using SEC are able to identify cancer cells, highlight active pathways in tumourigenesis, clinically distinguish cohorts and remain functionally active for further experiments.
Van Der Steen N, Keller K, Dekker H, et al., 2020, Crizotinib sensitizes the erlotinib resistant HCC827GR5 cell line by influencing lysosomal function, Journal of Cellular Physiology, Vol: 235, Pages: 8085-8097, ISSN: 0021-9541
In non‐small cell lung cancer, sensitizing mutations in epidermal growth factor receptor (EGFR) or cMET amplification serve as good biomarkers for targeted therapies against EGFR or cMET, respectively. Here we aimed to determine how this different genetic background would affect the interaction between the EGFR‐inhibitor erlotinib and the cMET‐inhibitor crizotinib. To unravel the mechanism of synergy we investigated the effect of the drugs on various parameters, including cell cycle arrest, migration, protein phosphorylation, kinase activity, the expression of drug efflux pumps, intracellular drug concentrations, and live‐cell microscopy. We observed additive effects in EBC‐1, H1975, and HCC827, and a strong synergism in the HCC827GR5 cell line. This cell line is a clone of the HCC827 cells that harbor an EGFR exon 19 deletion and has been made resistant to the EGFR‐inhibitor gefitinib, resulting in cMET amplification. Remarkably, the intracellular concentration of crizotinib was significantly higher in HCC827GR5 compared to the parental HCC827 cell line. Furthermore, live‐cell microscopy with a pH‐sensitive probe showed a differential reaction of the pH in the cytoplasm and the lysosomes after drug treatment in the HCC827GR5 in comparison with the HCC827 cells. This change in pH could influence the process of lysosomal sequestration of drugs. These results led us to the conclusion that lysosomal sequestration is involved in the strong synergistic reaction of the HCC827GR5 cell line to crizotinib–erlotinib combination. This finding warrants future clinical studies to evaluate whether genetic background and lysosomal sequestration could guide tailored therapeutic interventions.
Liu DSK, Prado MM, Giovannetti E, et al., 2019, Can circulating tumor and exosomal nucleic acids act as biomarkers for pancreatic ductal adenocarcinoma?, Expert Review of Molecular Diagnostics: new diagnostic technologies are set to revolutionise healthcare, Vol: 19, Pages: 553-558, ISSN: 1473-7159
El Hassouni B, Li Petri G, Liu DSK, et al., 2019, Pharmacogenetics of treatments for pancreatic cancer, Expert Opinion on Drug Metabolism and Toxicology, Vol: 15, Pages: 437-447, ISSN: 1742-5255
Introduction: Despite clinical efforts, pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. The scarcity of effective therapies can be reflected by the lack of reliable biomarkers to adapt anticancer drugs prescription to tumors’ and patients’ features.Areas covered: Pharmacogenetics should provide the way to select patients who may benefit from a specific therapy that best matches individual and tumor genetic profile, but it has not yet led to gains in outcome. This review describes PDAC pharmacogenetics findings, critically reappraising studies on polymorphisms and -omics profiles correlated to response to gemcitabine, FOLFIRINOX, and nab-paclitaxel combinations, as well as limitations of targeted therapies. Further, we question whether personalized approaches will benefit patients to any significant degree, supporting the need of new strategies within well-designed trials and validated genomic tests for treatment decision-making.Expert opinion: A major challenge in PDAC is the identification of subgroups of patients who will benefit from treatments. Minimally-invasive tests to analyze biomarkers of drug sensitivity/toxicity should be developed alongside anticancer treatments. However, progress might fall below expectations because of tumor heterogeneity and clonal evolution. Whole-genome sequencing and liquid biopsies, as well as prospective validation in selected cohorts, should overcome the limitations of traditional pharmacogenetic approaches.
Liu D, Ellis H, 2016, The mystery of the thymus gland, CLINICAL ANATOMY, Vol: 29, Pages: 679-684, ISSN: 0897-3806
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- Citations: 5
Liu D, Cockbain A, Dexter S, et al., 2016, The modern minimally-invasive management of Boerhaave's Syndrome, International Surgical Congress of the Association-of-Surgeons-of-Great-Britain-and-Ireland, Publisher: WILEY-BLACKWELL, Pages: 183-183, ISSN: 0007-1323
Liu D, Patil A, Ariyanayagam T, et al., 2010, ROUTINE MALE CIRCUMCISION IN THE YOUNG: IS IT TIME TO RECONSIDER THE BENEFITS?, Publisher: NATURE PUBLISHING GROUP, Pages: 444-444, ISSN: 0031-3998
Patil A, Liu D, Ariyanayagam T, et al., 2010, IS DIFFICULTY FEEDING AN INDICATION FOR FRENULOTOMY IN PATIENTS WITH ANKYLOGLOSSIA?, Publisher: NATURE PUBLISHING GROUP, Pages: 517-517, ISSN: 0031-3998
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