Exeter Clinical Laboratory International (Blood Sciences, Genetics, Cellular Pathology & Microbiology)

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Research outputs from the Pathology/Exeter Clinical Laboratory department at the RD&E. For more information about Exeter Clinical Laboratory, please visit their website: http://www.exeterlaboratory.com/

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    ST6GAL1-mediated aberrant sialylation promotes prostate cancer progression
    (Wiley, 2023-09-01) Scott, E.; Archer Goode, E.; Garnham, R.; Hodgson, K.; Orozco-Moreno, M.; Turner, H.; Livermore, K.; Putri Nangkana, K.; Frame, F. M.; Bermudez, A.; Jose Garcia Marques, F.; McClurg, U. L.; Wilson, L.; Thomas, H.; Buskin, A.; Hepburn, A.; Duxfield, A.; Bastian, K.; Pye, H.; Arredondo, H. M.; Hysenaj, G.; Heavey, S.; Stopka-Farooqui, U.; Haider, A.; Freeman, A.; Singh, S.; Johnston, E. W.; Punwani, S.; Knight, B.; McCullagh, P.; McGrath, J.; Crundwell, M.; Harries, L.; Heer, R.; Maitland, N. J.; Whitaker, H.; Pitteri, S.; Troyer, D. A.; Wang, N.; Elliott, D. J.; Drake, R. R.; Munkley, J.
    Aberrant glycosylation is a universal feature of cancer cells, and cancer-associated glycans have been detected in virtually every cancer type. A common change in tumour cell glycosylation is an increase in α2,6 sialylation of N-glycans, a modification driven by the sialyltransferase ST6GAL1. ST6GAL1 is overexpressed in numerous cancer types, and sialylated glycans are fundamental for tumour growth, metastasis, immune evasion, and drug resistance, but the role of ST6GAL1 in prostate cancer is poorly understood. Here, we analyse matched cancer and normal tissue samples from 200 patients and verify that ST6GAL1 is upregulated in prostate cancer tissue. Using MALDI imaging mass spectrometry (MALDI-IMS), we identify larger branched α2,6 sialylated N-glycans that show specificity to prostate tumour tissue. We also monitored ST6GAL1 in plasma samples from >400 patients and reveal ST6GAL1 levels are significantly increased in the blood of men with prostate cancer. Using both in vitro and in vivo studies, we demonstrate that ST6GAL1 promotes prostate tumour growth and invasion. Our findings show ST6GAL1 introduces α2,6 sialylated N-glycans on prostate cancer cells and raise the possibility that prostate cancer cells can secrete active ST6GAL1 enzyme capable of remodelling glycans on the surface of other cells. Furthermore, we find α2,6 sialylated N-glycans expressed by prostate cancer cells can be targeted using the sialyltransferase inhibitor P-3F(AX) -Neu5Ac. Our study identifies an important role for ST6GAL1 and α2,6 sialylated N-glycans in prostate cancer progression and highlights the opportunity to inhibit abnormal sialylation for the development of new prostate cancer therapeutics. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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    Pretracheal ectopic thymoma: A diagnostic challenge in endobronchial ultrasound-guided transbronchial needle aspiration cytology
    (Wiley, 2022-07-01) George, E.; Khan, R.; Powari, M.; Dorey, N.
    Ectopic thymomas (ETs) are rare thymic neoplasms that arise from atypical anatomical sites and present a diagnostic challenge for clinicians as they can be mistaken for other pathological entities on fine needle aspiration (FNA) cytology.
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    A feasibility study of multisite networked digital pathology reporting in England
    (Medknow Publications, 2022-01-01) Mayall, Frederick; Smethurst, Hanne-Brit; Semkin, Leonid; Mandalia, Trupti; Sohail, Muhammed; Hadden, Rob; Biddlestone, Leigh
    Background: The objective of the project was to evaluate the feasibility of introducing a single-networked digital histopathology reporting platform in the Southwest Peninsula region of England by allowing pathologists to experience the technology and recording their perceptions. This information was then used in planning future service development. The project was funded by the National Health Service (NHS) Peninsula Cancer Alliance and took place in 2020 during the COVID-19 pandemic. Materials and Methods: Digital slides of 500 cases from Taunton were reported remotely in Truro, Plymouth, Exeter, Bristol, or Bath by using a single remote reporting platform located on the secure Health and Social Care Network (HSCN) that links NHS sites. These were mainly small gastrointestinal, skin, and gynecological specimens. The digital diagnoses were compared with the diagnoses issued on reporting the glass slides. At the end of the project, the pathologists completed a Google Forms questionnaire of their perceptions of digital pathology. The results were presented at a meeting with the funder and discussed. Results: From the 500 cases there were nine cases of significant diagnostic discrepancy, seven of which involved the misrecognition of Helicobacter pylori in gastric biopsies. The questionnaire at the end of the project showed that there was a general agreement that the platform was easy to use, and the image quality was acceptable. It was agreed that extra work, such as deeper levels, was easy to request on the software platform. Most pathologists did not agree that digital reporting was quicker than glass slide reporting. Some were less confident in their digital diagnoses than glass diagnoses. They agreed that some types of specimens cannot easily be reported digitally. All users indicated that they would like to report at least half of their work digitally in the future if they could, and all strongly agreed that digital pathology would improve access to expert opinions, teaching, and multidisciplinary meetings. It was difficult to find pathologists with time to undertake remote digital reporting, in addition to their existing commitments. Conclusions: Overall, the pathologists developed a positive perception of digital pathology and wished to continue using it.
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    Corrigendum to "Pathological chemotherapy response score is prognostic in tubo-ovarian high-grade serous carcinoma: A systematic review and meta-analysis of individual patient data" Gynecol. Oncol. 154 (2019) 441-448
    (Elsevier, 2021-04-01) Cohen, Paul A.; Powell, Aime; Böhm, Steffen; Gilks, C. Blake; Stewart, Colin J. R.; Meniawy, Tarek M.; Bulsara, Max; Avril, Stefanie; Brockbank, Eleanor C.; Bosse, Tjalling; de Azevedo Focchi, Gustavo Rubino; Ganesan, Raji; Glasspool, Rosalind M.; Howitt, Brooke E.; Kim, Hyun-Soo; Lee, Jung-Yun; Le, Nhu D.; Lockley, Michelle; Manchanda, Ranjit; Mandalia, Trupti; McCluggage, W. Glenn; McNeish, Iain; Midha, Divya; Srinivasan, Radhika; Tan, Yun Yi; van der Griend, Rachael; Yunokawa, Mayu; Zannoni, Gian F.; Singh, Naveena
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    Validating the positivity thresholds of drug-tolerant anti-infliximab and anti-adalimumab antibody assays
    (Wiley, 2021-01) Nice, Rachel; Chanchlani, Neil; Bewshea, Claire; Ahmad, Tariq; Goodhand, James R.; McDonald, Timothy J.; Perry, Mandy; Kennedy, Nicholas A.
    Background: When used proactively, drug-tolerant anti-tumour necrosis factor (TNF) antibody assays provide early opportunity to suppress immunogenicity. Aim: To validate positivity thresholds of IDKmonitor drug-tolerant anti-infliximab and -adalimumab antibody assays. Methods: We applied positivity thresholds, defined by testing sera from 498 anti-TNF naive healthy adults, from the Exeter Ten Thousand study to data from our therapeutic drug monitoring (TDM) service and Personalised Anti-TNF Therapy in Crohn's disease (PANTS) cohort to explore associations with drug level and treatment outcomes. Results: The 80% one-sided lower confidence interval of the 99th centile concentration for anti-infliximab and -adalimumab antibodies were lower than the manufacturers threshold of 10 arbitrary units (AU)/mL; 9 and 6 AU/mL, respectively. Using these new thresholds in the TDM cohort, more adalimumab- than infliximab- (11.2% [814/7272] vs 3.1% [390/12 683] P < 0.0001) treated patients were reclassified as antibody-positive. Adalimumab drug concentrations in this reclassified group (median 8.1, interquartile range [IQR] 5.5-11.0 mg/L) were lower than those below the new threshold (<5AU/mL) (median 9.9, IQR 7.1-13.0 mg/L; P < 0.0001), but higher than at the manufacturer's threshold (10-29 AU/mL) (median 5.9 mg/L, IQR 3.5-8.7; P < 0.0001). No difference in infliximab drug concentration was observed using the new or manufacturer's positivity threshold (P = 0.11). In the PANTS cohort, patients with anti-adalimumab antibody concentrations at or above the new threshold were more likely to be in primary non-response (25/68 [37%] vs. 64/332 [19%], P = 0.0035), and non-remission at week 54 (51/62 [82%] vs. 168/279 [60%], P = 0.0011), than patients with anti-drug antibody concentrations in the group below the new threshold (0-5 AU/mL); this was not seen for anti-infliximab antibodies. Conclusion: Laboratories should derive antibody positivity thresholds for assays they use. For adalimumab, low-concentration anti-drug antibodies were associated with lower drug levels and treatment failure.