Pancreatic cancer is detected late in the disease process and has an extremely poor prognosis. A blood-based biomarker that can enable early detection of disease, monitor response to treatment, and ...potentially allow for personalized treatment would be of great benefit. This review analyzes the literature regarding two potential biomarkers, circulating tumor cells (CTCs) and cell-free DNA (cfDNA), with regard to pancreatic ductal adenocarcinoma. The origin of CTCs and the methods of detection are discussed and a decade of research examining CTCs in pancreatic cancer is summarized, including both levels of CTCs and analyzing their molecular characteristics and how they may affect survival in both advanced and early disease and allow for treatment monitoring. The origin of cfDNA is discussed, and the literature over the past 15 years is summarized. This includes analyzing cfDNA for genetic mutations and methylation abnormalities, which have the potential to be used for the detection and prognosis of pancreatic ductal adenocarcinoma. However, the research certainly remains in the experimental stage, warranting future large trials in these areas.
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.
MicroRNA (miRNA) expression profiles have been described in pancreatic ductal adenocarcinoma (PDAC), but these have not been compared with pre-malignant pancreatic tumors. We wished to compare the ...miRNA expression signatures in pancreatic benign cystic tumors (BCT) of low and high malignant potential with PDAC, in order to identify miRNAs deregulated during PDAC development. The mechanistic consequences of miRNA dysregulation were further evaluated.
Tissue samples were obtained at a tertiary pancreatic unit from individuals with BCT and PDAC. MiRNA profiling was performed using a custom microarray and results were validated using RT-qPCR prior to evaluation of miRNA targets.
Widespread miRNA down-regulation was observed in PDAC compared to low malignant potential BCT. We show that amongst those miRNAs down-regulated, miR-16, miR-126 and let-7d regulate known PDAC oncogenes (targeting BCL2, CRK and KRAS respectively). Notably, miR-126 also directly targets the KRAS transcript at a "seedless" binding site within its 3'UTR. In clinical specimens, miR-126 was strongly down-regulated in PDAC tissues, with an associated elevation in KRAS and CRK proteins. Furthermore, miR-21, a known oncogenic miRNA in pancreatic and other cancers, was not elevated in PDAC compared to serous microcystic adenoma (SMCA), but in both groups it was up-regulated compared to normal pancreas, implicating early up-regulation during malignant change.
Expression profiling revealed 21 miRNAs down-regulated in PDAC compared to SMCA, the most benign lesion that rarely progresses to invasive carcinoma. It appears that miR-21 up-regulation is an early event in the transformation from normal pancreatic tissue. MiRNA expression has the potential to distinguish PDAC from normal pancreas and BCT. Mechanistically the down-regulation of miR-16, miR-126 and let-7d promotes PDAC transformation by post-transcriptional up-regulation of crucial PDAC oncogenes. We show that miR-126 is able to directly target KRAS; re-expression has the potential as a therapeutic strategy against PDAC and other KRAS-driven cancers.
The aim of the study was to identify plasma microRNA (miRNA) biomarkers for stratifying and monitoring patients with locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC) treated ...with FOLFIRINOX, and to investigate their functional roles.
FOLFIRINOX has become a standard therapy for patients with advanced PDAC and can be used to potentially downstage disease. However, only a subset of patients respond, and biomarkers to guide decision-making are urgently needed.
We used microarray-based profiling to discover deregulated miRNAs in pre- and postchemotherapy plasma samples from patients based on their progression-free survival (PFS) after FOLFIRINOX. Nine candidate plasma miRNAs were validated in an independent cohort (n = 43). The most discriminative plasma miRNA was correlated with clinicopathological factors and survival, and also investigated in an additional cohort treated with gemcitabine plus nab-paclitaxel. Expression patterns were further evaluated in matched tumor tissues. In vitro studies explored its function, key downstream gene-targets, and interaction with 5-fluorouracil, irinotecan, and oxaliplatin.
Plasma miR-181a-5p was significantly downregulated in non-progressive patients after FOLFIRINOX. In multivariate analysis, this decline correlated with improved PFS and overall survival, especially when combined with CA19-9 decline hazard ratio (HR) = 0.153, 95% confidence interval (CI), 0.067-0.347 and HR = 0.201, 95% CI, 0.070-0.576, respectively. This combination did not correlate with survival in patients treated with gemcitabine plus nab-paclitaxel. Tissue expression of miR-181a-5p reflected plasma levels. Inhibition of miR-181a-5p coupled with oxaliplatin exposure in pancreatic cell lines decreased cell viability.
Plasma miR-181a-5p is a specific biomarker for monitoring FOLFIRINOX response. Decline in plasma miR-181a-5p and CA19-9 levels is associated with better prognosis after FOLFIRINOX and may be useful for guiding therapeutic choices and surgical exploration.
TGF-β/Activin induces epithelial-to-mesenchymal transition and stemness in pancreatic ductal adenocarcinoma (PDAC). However, the microRNAs (miRNAs) regulated during this response have remained yet ...undetermined. Here, we show that TGF-β transcriptionally induces MIR100HG lncRNA, containing miR-100, miR-125b and let-7a in its intron, via SMAD2/3. Interestingly, we find that although the pro-tumourigenic miR-100 and miR-125b accordingly increase, the amount of anti-tumourigenic let-7a is unchanged, as TGF-β also induces LIN28B inhibiting its maturation. Notably, we demonstrate that inactivation of miR-125b or miR-100 affects the TGF-β-mediated response indicating that these miRNAs are important TGF-β effectors. We integrate AGO2-RIP-seq with RNA-seq to identify the global regulation exerted by these miRNAs in PDAC cells. Transcripts targeted by miR-125b and miR-100 significantly overlap and mainly inhibit p53 and cell-cell junctions' pathways. Together, we uncover that TGF-β induces an lncRNA, whose encoded miRNAs, miR-100, let-7a and miR-125b play opposing roles in controlling PDAC tumourigenesis.
Polymorphic microbes: a new emerging hallmark of cancer Lythgoe, Mark P.; Mullish, Benjamin H.; Frampton, Adam E. ...
Trends in microbiology (Regular ed.),
December 2022, 2022-12-00, Letnik:
30, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Recognition of the microbiome (and ‘polymorphic microbes’ within them) as a new emerging hallmark of cancer reflects a wide body of rapidly evolving research. Microbes may be directly carcinogenic, ...impact host immune responses to promote malignancy, and may be key effectors in determining the efficacy of anticancer therapy. Manipulation of the microbiome is showing promise as an opportunity to influence cancer outcomes.
The growth arrest-specific transcript 5 gene (GAS5) encodes a long noncoding RNA (lncRNA) and hosts a number of small nucleolar RNAs (snoRNAs) that have recently been implicated in multiple cellular ...processes and cancer. Here, we investigate the relationship between DNA damage, p53, and the GAS5 snoRNAs to gain further insight into the potential role of this locus in cell survival and oncogenesis both in vivo and in vitro.
We used quantitative techniques to analyse the effect of DNA damage on GAS5 snoRNA expression and to assess the relationship between p53 and the GAS5 snoRNAs in cancer cell lines and in normal, pre-malignant, and malignant human colorectal tissue and used biological techniques to suggest potential roles for these snoRNAs in the DNA damage response.
GAS5-derived snoRNA expression was induced by DNA damage in a p53-dependent manner in colorectal cancer cell lines and their levels were not affected by DICER. Furthermore, p53 levels strongly correlated with GAS5-derived snoRNA expression in colorectal tissue.
In aggregate, these data suggest that the GAS5-derived snoRNAs are under control of p53 and that they have an important role in mediating the p53 response to DNA damage, which may not relate to their function in the ribosome. We suggest that these snoRNAs are not processed by DICER to form smaller snoRNA-derived RNAs with microRNA (miRNA)-like functions, but their precise role requires further evaluation. Furthermore, since GAS5 host snoRNAs are often used as endogenous controls in qPCR quantifications we show that their use as housekeeping genes in DNA damage experiments can lead to inaccurate results.
We Published a step–up approach for robotic training in hepato-pancreato-biliary (HPB) surgery has been previously. The approach was mostly based on personal experience and communications between ...experts and needed appraisal and validation by the HPB surgical community. At the Great Britain and Ireland HPB Association (GBIHPBA) robotic HPB meeting held in Coventry, UK in October 2022, the authors sought consensus from the live audience, with an open forum for answering key questions. The aim of this exercise was to appraise the step-up approach, and in turn, lay the foundation for a more substantial UK robotic HPB surgical curriculum.
The study was conducted using VEVOX online polling platform at the October 2022 GBIHPBA robotic HPB meeting in Coventry, UK. The questionnaire was designed based on a literature search and was externally validated. The data were collated and analysed to assess patterns of response.
A median (IQR) of 104 (96–117) responses were generated for each question. 93 consultants and 61 trainees were present Over 90% were in favour of a standardised training pathway. 93.6% were in favour of the proposed step-up approach, with a significant number (67.3%; p < 0.001) considering three levels of case complexity.
The survey shows a favourable outlook on adopting step-up training in robotic HPB surgery. Ongoing monitoring of progress, clinical outcomes, and collaboration among surgeons and units will bolster this evidence, potentially leading to an official UK robotic HPB curriculum.
Gene of the month: HGF Fajardo-Puerta, Ana Belen; Mato Prado, Mireia; Frampton, Adam E ...
Journal of clinical pathology,
07/2016, Letnik:
69, Številka:
7
Journal Article
Recenzirano
Hepatocyte growth factor (HGF) is a multifunctional cytokine with important roles in cell proliferation, survival, motility and morphogenesis. Secreted by cells of mesenchymal origin, HGF is the ...specific ligand for the tyrosine-kinase receptor c-MET (cellular mesenchymal-epithelial transition), also called MET, which is expressed in different types of epithelial, endothelial and haematopoietic progenitor cells. The HGF/MET axis is involved in several biological processes, such as embryogenesis, organogenesis, adult tissue regeneration (including wound healing and liver regeneration) and carcinogenesis, for both solid and haematological malignancies.(1 2) HGF and its particular interaction with the MET receptor have been extensively investigated in the last decades and remain the focus of numerous clinical trials.(3-8) This short review focuses on HGF structure and function, as well as its roles in liver regeneration and different types of tumours.
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