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Liverpool, United Kingdom

Tonack S.,University of Liverpool | Jenkinson C.,University of Liverpool | Cox T.,University of Liverpool | Elliott V.,University of Liverpool | And 8 more authors.
British Journal of Cancer | Year: 2013

Background: The aims of our study were to identify serum biomarkers that distinguish pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) patients from benign pancreatic disease patients and healthy subjects, and to assess the effects of jaundice on biomarker performance. Methods: Isobaric tags for relative and absolute quantification were used to compare pooled serum and pancreatic juice samples from a test set of 59 and 25 subjects, respectively. Validation was undertaken in 113 independent subjects. Results: Candidate proteins Complement C5, inter-α-trypsin inhibitor heavy chain H3, α1-β glycoprotein and polymeric immunoglobulin receptor were elevated in cancer, as were the reference markers CA19-9 and Reg3A. Biliary obstruction had a significant effect on the performance of the markers, in particular within the PDAC group where the presence of jaundice was associated with a significant increase in the levels of all six proteins (P<0.01). Consequently, in the absence of jaundice, proteins showed reduced sensitivity for PDAC patients over benign subjects and healthy controls (HCs). Similarly, in the presence of jaundice, markers showed reduced specificity for PDAC patients over benign subjects with jaundice. Combining markers enabled improved sensitivity for non-jaundiced PDAC patients over HCs and improved specificity for jaundiced PDAC patients over jaundiced benign disease subjects.Conclusions:The presence-absence of jaundice in the clinical scenario severely impacts the performance of biomarkers for PDAC diagnosis and has implications for their clinical translation. © 2013 Cancer Research UK. All rights reserved.

Chadwick J.,University of Liverpool | Jones M.,University of Liverpool | Mercer A.E.,Center for Drug Safety Science | Park B.K.,Center for Drug Safety Science | And 2 more authors.
Bioorganic and Medicinal Chemistry | Year: 2010

A series of artemisinin-spermidine conjugates designed to utilise the upregulated polyamine transporter found in cancer cells have been prepared. These conjugates were evaluated against human promyelocytic leukaemia HL-60 cells and chloroquine-sensitive 3D7 Plasmodium falciparum and several show promising anticancer and antimalarial activity. Although some limitations in this vector-based approach are apparent, a number of high potency Boc-protected analogues were identified with activity against malaria parasites as low as 0.21 nM. © 2010 Elsevier Ltd. All rights reserved.

Tonack S.,University of Liverpool | Patel S.,University of Liverpool | Jalali M.,University of Liverpool | Nedjadi T.,University of Liverpool | And 5 more authors.
World Journal of Gastroenterology | Year: 2011

To establish stable tetracycline-inducible pancreatic cancer cell lines.Suit-2, MiaPaca-2, and Panc-1 cells were transfected with a second generation reverse tetra-cycline-controlled transactivator protein (rtTA2S-M2), under the control of either a cytomegalovirus (CMV) or a chicken β-actin promoter, and the resulting clones were characterised. Use of the chicken (β-actin) promoter proved superior for both the production and maintenance of doxycycline-inducible cell lines. The system proved versatile, enabling transient inducible expression of a variety of genes, including GST-P, CYP2E1, S100A6, and the actin capping protein, CapG. To determine the physiological utility of this system in pancreatic cancer cells, stable inducible CapG expressors were established. Overexpressed CapG was localised to the cytoplasm and the nuclear membrane, but was not observed in the nucleus. High CapG levels were associated with enhanced motility, but not with changes to the cell cycle, or cellular proliferation. In CapG-overexpressing cells, the levels and phosphorylation status of other actin-moduating proteins (Cofilin and Ezrin/Radixin) were not altered. However, preliminary analyses suggest that the levels of other cellular proteins, such as ornithine aminotransferase and enolase, are altered upon CapG induction. We have generated pancreatic-cancer derived cell lines in which gene expression is fully controllable. © 2011 Baishideng. All rights reserved.

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