• Invasive phenotype of primary human prostatic epithelial cells.

      Scott, L J; Clarke, Noel W; Sharrard, M S; George, N J; Lang, S H; Department of Urology and Paterson Institute CRC Research Laboratories, Christie Hospital, Manchester, UK. (2000-12)
    • Inverse relationship between hyaluronan and collagens in development and angiogenesis.

      Rooney, P; Kumar, Shant; Department of Pathological Sciences, University of Manchester, UK. (1993-08)
      The extracellular matrix plays a vital role in regulating normal tissue development and function--largely via the specific arrangement of macromolecules such as collagens, proteoglycans, glycosaminoglycans and glycoproteins. Previous reports have concentrated on associations between combinations of collagens/proteoglycans, collagens/glycoproteins and proteoglycans/glycosaminoglycans whilst little information is available on associations between collagens and free glycosaminoglycans. In this review, we discuss possible associations between collagens and the glycosaminoglycan hyaluronan; macromolecules which are known to exhibit changes in amount and composition during development and under pathological conditions. We demonstrate two types of collagen/hyaluronan association in vivo: the first, during the formation of extracellular matrix structures where neither collagens nor hyaluronan are degraded, resulting in the regulation of collagen fibrillogenesis, and the second, involving an inverse correlation between collagen synthesis and hyaluronan degradation and vice versa. We suggest that associations between collagens and hyaluronan play an important role in the initiation and maintenance of angiogenesis and put forward a model of cartilage vascularisation which relies on these associations.
    • Investigating online adaptive workflows for prostate patients on the MR-Linac: an in-silico study.

      Jones, S; Chuter, Robert; Pollitt, Andrew; Warren, M; McWilliam, Alan; University of Liverpool, Directorate of Medical Imaging and Radiotherapy, Liverpool (2018)
    • Investigating radiotherapy response in a novel syngeneic model of prostate cancer

      Haughey, C. M.; Mukherjee, D.; Steele, R. E.; Popple, A.; Dura-Perez, L.; Pickard, A.; Patel, M.; Jain, S.; Mullan, P. B.; Williams, R.; et al. (2020)
      The prostate cancer (PCa) field lacks clinically relevant, syngeneic mouse models which retain the tumour microenvironment observed in PCa patients. This study establishes a cell line from prostate tumour tissue derived from the Pten-/-/trp53-/- mouse, termed DVL3 which when subcutaneously implanted in immunocompetent C57BL/6 mice, forms tumours with distinct glandular morphology, strong cytokeratin 8 and androgen receptor expression, recapitulating high-risk localised human PCa. Compared to the commonly used TRAMP C1 model, generated with SV40 large T-antigen, DVL3 tumours are immunologically cold, with a lower proportion of CD8+ T-cells, and high proportion of immunosuppressive myeloid derived suppressor cells (MDSCs), thus resembling high-risk PCa. Furthermore, DVL3 tumours are responsive to fractionated RT, a standard treatment for localised and metastatic PCa, compared to the TRAMP C1 model. RNA-sequencing of irradiated DVL3 tumours identified upregulation of type-1 interferon and STING pathways, as well as transcripts associated with MDSCs. Upregulation of STING expression in tumour epithelium and the recruitment of MDSCs following irradiation was confirmed by immunohistochemistry. The DVL3 syngeneic model represents substantial progress in preclinical PCa modelling, displaying pathological, micro-environmental and treatment responses observed in molecular high-risk disease. Our study supports using this model for development and validation of treatments targeting PCa, especially novel immune therapeutic agents.
    • Investigating the role of focal adhesion kinase in regulating CSC activity in invasive ductal carcinoma

      Timbrell, S; Aglan, H; Cramer, A; Foden, P; Weaver, D; Pachter, J; Farnie, Gillian; Clarke, Robert B; Bundred, Nigel J; Breast Biology Group, The University of Manchester, Manchester (2019)
    • An investigation into dose optimisation for imaging root canal anatomy using cone beam CT

      McGuigan, M.; Theodorakou, Chrysoula; Duncan, H. F.; Jonathan, D.; Sengupta, A.; Keith, H.; Dublin Dental University Hospital, Trinity College Dublin, Dublin, Ireland. (2020)
      OBJECTIVES: To identify a dose as low as diagnostically acceptable and a threshold level of image quality for CBCT imaging root canals, using maxillary first molar (M1M) second mesio-buccal (MB2) canals of varying complexity for two CBCT scanners. METHODS: Dose-area product (DAP) and contrast-to-noise ratio (CNR) were measured for two scanners at a range of exposure parameters. Subjective-image-quality assessment (SIQA) at the same exposures was performed for 3 M1M's of varying MB2 complexity, positioned in a anthropomorphic phantom. Nine raters (three endodontists, three dental radiologists and three junior staff) assessed canal visibility, using a five-point confidence scale rating (CSR). RESULTS: Identification of simple-moderate MB2 canal complexity was achieved at a range of protocols, with DAP values of /=209.3 mGy cm(2) and "/=203.2 mGy cm(2) and CNRs of 3 and 7.6 for Promax((R))3D and Accuitomo-F170((R)) respectively. For complex canal anatomy
    • An investigation into the dosage delivered by certain techniques in the radiation therapy of carcinoma cervix.

      Sandler, Bernard; Christie Hospital and Holt Radium Institute, Manchester (1938)
    • Investigation into the educational needs of non-specialised staff regarding brain metastases and the provision of an education package.

      Emerson, Julie; Robson, Sara; Molloy, Liz; McBain, Catherine A; Christie Hospital NHS Foundation Trust, Manchester (2017)
    • An investigation into the effects of prior irradiation to the tumour mass on murine TIL expansion

      Azizi, Alexander; Cheadle, Eleanor J; Popple, Amy; Illidge, Timothy M; Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK (2018)
    • An investigation into the levels of radiation exposure in diagnostic examinations involving fluoroscopy.

      Rowley, K A; Hill, S J; Watkins, R A; Moores, B M (1987-02)
      In order to investigate the levels of radiation exposure resulting from fluoroscopic examinations, area-exposure product measurements were performed on 6532 patients whilst undergoing a variety of examinations at a large district general hospital. Results for both the same and different types of examinations, performed in two different X-ray rooms by a number of different radiologists, are compared in order to highlight some of the factors which influence the wide variations in patient exposure which frequently occur in radiological examinations. Variations in exposure of patients of different weights are also presented.
    • Investigation of a new pure antiestrogen (ICI 182780) in women with primary breast cancer.

      DeFriend, David J; Howell, Anthony; Nicholson, R I; Anderson, Elizabeth; Dowsett, M; Mansel, Robert E; Blamey, R W; Bundred, Nigel J; Robertson, J F; Saunders, C; et al. (1994-01-15)
      We have conducted a clinical trial of a novel pure antiestrogen, 7 alpha-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]estra-1,3,5,(1 0)-triene-3,17 beta-diol (ICI 182780), to assess its tolerance, pharmacokinetics, and short term biological effects in women with primary breast cancer. Fifty-six patients were randomized to either a control group (n = 19), in which they received no preoperative treatment, or a treatment group (n = 37), in which they received daily i.m. injections of ICI 182780 at doses of 6 mg (n = 21) or 18 mg (n = 16) for 7 days prior to primary breast surgery. Serum drug concentrations, gonadotropin levels, and sex hormone-binding globulin levels were measured during the study period by radioimmunoassay. Expression of estrogen receptors (ER), progesterone receptors, the estrogen-induced protein pS2, and the cell proliferation-related antigen Ki67 was determined immunocytochemically in pre- and poststudy tumor samples. Treatment with ICI 182780 caused no serious drug-related adverse events and had no effect on serum gonadotropin or sex hormone-binding globulin levels. Minor adverse events occurred in 5 patients receiving the 6-mg dose and 3 patients receiving the 18-mg dose. The serum concentration of ICI 182780 was dose dependent but showed variation between individuals. There was evidence of an approximately 3-fold drug accumulation over the short treatment period but steady state levels were not reached by the end of the 7 days. In patients with ER-positive tumors, treatment with ICI 182780 was associated with significant reductions in the tumor expression of ER (median ER index, 0.72 before versus 0.02 after treatment; P < 0.001), progesterone receptor (median progesterone receptor index, 0.50 before versus 0.01 after treatment; P < 0.05), and Ki67 (median Ki67 labeling index, 3.2 before versus 1.1 after treatment; P < 0.05). Treatment with ICI 182780 also resulted in a significant reduction in pS2 expression (P < 0.05) but this appeared unrelated to tumor ER status. In conclusion, ICI 182780 was well tolerated after short term administration and produced demonstrable antiestrogenic effects in human breast tumors in vivo, without showing evidence of agonist activity. These properties identify ICI 182780 as a candidate agent with which to evaluate whether a pure estrogen antagonist offers any additional benefit in the treatment of human breast cancer over conventional nonsteroidal antiestrogens, typified by tamoxifen, which exhibit variable degrees of agonist activity.
    • Investigation of a patient reported outcome tool to assess radiotherapy-related toxicity prospectively in patients with lung cancer.

      Christodoulou, Marianna; McCloskey, Paula; Stones, Nicola; Bayman, Neil A; Burt, Paul A; Chittalia, Abbas; Harris, Maggie A; Lee, Lip W; Pemberton, Laura S; Sheikh, Hamid Y; et al. (2014-08-05)
      There is a paucity of data regarding the feasibility and relevance of Patient Reported Outcome (PRO) tools to assess radiotherapy-related toxicity in lung cancer.
    • Investigation of dose homogeneity in paediatric anthropomorphic phantoms for a simple total body irradiation technique.

      Vollans, S E; Perrin, Bruce A; Wilkinson, James M; Gattamaneni, Rao; Deakin, David P; Department of Clinical Oncology, Christie Hospital NHS Trust, Manchester, UK. (2000-03)
      The technique for treating total body irradiation patients used at the centre involves no compensation for the inhomogeneity of patient shape. Dose is prescribed to the lung, and monitor units are derived from standard data depending on the external dimensions of the patient at nipple level. Dose measurements were made during standard treatments on three paediatric anthropomorphic phantoms representing children of 5, 10 and 15 years of age. The results confirmed that the measured dose to the lung was within 4% of the prescribed dose, and dose homogeneity was within +/- 5%, excluding the neck, where the higher measured doses were still within tissue tolerance.
    • Investigation of downstream target genes of PAX3c, PAX3e and PAX3g isoforms in melanocytes by microarray analysis.

      Wang, Qiuyu; Kumar, Shant; Mitsios, Nick; Slevin, Mark; Kumar, Patricia; School of Biology, Chemistry and Health Science, Manchester Metropolitan University, Manchester, United Kingdom. (2007-03-15)
      PAX3 encodes a transcription factor, which with Zic1 is necessary for induction of the neural crest during early embryonic development. There are 7 human PAX3 isoforms (a-h). PAX3e is the full length isoform comprising 10 exons. PAX3c comprises 8 exons plus 5 codons of intron 8, while PAX3g has a truncated transactivation domain. Previous studies by us indicated that these isoforms have different activities in melanocytes in vitro. In this study, a mouse gene oligo array ( approximately 7.5 k oligos), from the Human Genome Mapping Project (HGMP) Resource Centre, was used to screen for alterations in downstream gene expression in PAX3c, PAX3e and PAX3g melanocyte transfectants, compared with empty vector controls. The data analyses identified 109 genes up or downregulated, at least 2-fold, and involved in cell differentiation, proliferation, migration, adhesion, apoptosis and angiogenesis. Semi-quantitative RT-PCR and Western blotting confirmed the changes identified by microarrays for several putative targets of PAX3, including Met, MyoD and Muc18, and previously undescribed targets, including Dhh, Fgf17, Kitl and Rac1. Thus, our data reveal that PAX3 isoforms regulate distinct but overlapping sets of genes in melanocytes in vitro.
    • Investigation of mammary epithelial cell-bone marrow stroma interactions using primary human cell culture as a model of metastasis.

      Brooks, B; Bundred, Nigel J; Howell, Anthony; Lang, Shona H; Testa, Nydia G; CRC Department of Experimental Haematology, Paterson Institute for Cancer Research, Manchester, UK. ptbmb@liv.ac.uk (1997-11-27)
      A model has been established using primary human cell culture to study the cell biology of breast cancer metastasis to bone marrow. Mammary epithelia were obtained in single cell suspension from tumour (macroscopically involved), benign (macroscopically uninvolved) and normal (reduction mammoplasty) breast tissue as well as from locally involved lymph nodes. Stromal layers were generated from long-term cultures of human bone marrow or from mammary fibroblasts derived from normal or malignant tissue. The interaction between epithelia and stroma has been studied in terms of adhesion of the epithelia to the stroma and their subsequent growth in co-culture. Our results show that when assayed up to 9 hr after plating, epithelial cells from malignant tissue (14 primary tumours and 9 metastases in lymph nodes) displayed a significant preference for adhesion to bone marrow stroma compared with mammary fibroblasts. In contrast, epithelial cells from 4 normal and 2 of 4 benign samples showed no significant preferential adherence. Subsequent co-culture of mammary epithelia with each of the 3 stromal layers revealed that under serum-free, in vitro conditions, bone marrow stromal layers did not provide an advantageous environment for colony growth, in contrast to their ability to provide a preferential substratum for adhesion.
    • Investigation of myositis and scleroderma specific autoantibodies in patients with lung cancer.

      Betteridge, Z; Priest, L; Cooper, R; McHugh, N; Blackhall, Fiona H; Lamb, J; Department of Pharmacy and Pharmacology, University of Bath, Bath, UK (2018-08-09)
      The close temporal association between onset of some connective tissue diseases and cancer suggests a paraneoplastic association. Adult patients with scleroderma with anti-RNA polymerase III autoantibodies and adult patients with dermatomyositis with anti-transcriptional intermediary factor 1 (anti-TIF1) or anti-nuclear matrix protein 2 (anti-NXP2) autoantibodies have a significantly increased risk of developing cancer. Autoantibodies may serve as biomarkers for early detection of cancer and also could be relevant for prediction of responses to immune therapies. We aimed to test whether myositis and scleroderma specific or associated autoantibodies are detectable in individuals with lung cancer.
    • Investigation of the epithelial to mesenchymal transition markers S100A4, vimentin and Snail1 in gastroesophageal junction tumors.

      Mirza, A; Foster, L; Valentine, Helen R; Welch, I; West, Catharine M L; Pritchard, S; Department of Gastrointestinal Surgery, University Hospital of South Manchester, Manchester, UK; Department of Histopathology, University Hospital of South Manchester, Manchester, UK. (2014-07)
      Epithelial to mesenchymal transition (EMT) promotes tumor progression and invasion. As no study has focused on gastroesophageal junction (GEJ) tumors, the expression of three EMT-related proteins (S100A4, vimentin, and Snail1) was investigated with the aim of assessing their pathologic and prognostic significance. Resection specimens were obtained from 104 patients who underwent surgery for GEJ adenocarcinoma, without preoperative chemotherapy. Three tissue cores were obtained from each of the tumor body (TB), luminal surface (LS), and invasive edge (IE) to produce tissue microarrays, and immunohistochemical staining was performed. The microarrays were scored independently by two observers. The demographic and histopathologic details of the patients were collected. Overall positive expression was observed in 88 (S100A4, 85%), 16 (vimentin, 14%), and 92 (Snail1, 89%) tumors. Staining for S100 A4 was positive in 79 (76%) of TB, 69 (66%) of IE, and 69 (66%) of LS specimens. Staining for vimentin was positive in 7 (6%) of TB, 11 (11%) of IE, and 5 (5%) of LS specimens. Staining for Snail1 was positive in 83 (80%) of TB, 51 (49%) of IE, and 78 (75%) of LS specimens. Positive staining of TB for S100A4 (P = 0.04) and Snail1 at IE (P = 0.01) was associated with involvement of circumferential resection margins. Positive staining for S100A4 in the TB (P = 0.02) and LS (P = 0.01) was associated with poor 5-year overall survival. Vimentin had no statistically significant relationships with pathologic factors or outcome. The acquisition of mesenchymal protein S100A4 is associated with a poor prognosis in patients with GEJ tumors who undergo potentially curative surgery, and LS samples can be used to obtain prognostic information. Increased EMT-related protein expression (S100A4, Snail1) is associated with the involvement of circumferential resection margin.
    • An investigation of the radiation dose to staff during cardiac radiological studies.

      Jeans, Steve; Faulkner, K; Love, H; Bardsley, R; Regional Department of Medical Physics and Bioengineering, Christie Hospital and Holt Radium Institute, Withington, Manchester M20 9BX (1985-05)
      Measurements of radiation distributions in the vicinity of the couch were undertaken for a number of projections commonly employed during cardiac radiological studies. Three types of investigations were considered; cardiac catheterisations, pacemaker implants and percutaneous transluminal coronary angioplasties. The radiation dose to staff involved in these procedures was estimated. For each group of staff, the maximum annual workload and the workload which would necessitate an individual becoming a classified radiation worker may be deduced from an expression given in the text.
    • An investigation of the RWPE prostate derived family of cell lines using FTIR spectroscopy.

      Baker, M J; Clarke, C; Démoulin, D; Nicholson, J M; Lyng, F M; Byrne, H J; Hart, C Anthony; Brown, Michael D; Clarke, Noel W; Gardner, Peter; et al. (2010-05-26)
      Interest in developing robust, quicker and easier diagnostic tests for cancer has lead to an increased use of Fourier transform infrared (FTIR) spectroscopy to meet that need. In this study we present the use of different experimental modes of infrared spectroscopy to investigate the RWPE human prostate epithelial cell line family which are derived from the same source but differ in their mode of transformation and their mode of invasive phenotype. Importantly, analysis of the infrared spectra obtained using different experimental modes of infrared spectroscopy produces similar results. The RWPE family of cell lines can be separated into groups based upon the method of cell transformation rather than the resulting invasiveness/aggressiveness of the cell line. The study also demonstrates the possibility of using a genetic algorithm as a possible standardised pre-processing step and raises the important question of the usefulness of cell lines to create a biochemical model of prostate cancer progression.
    • Investigation of the survivorship needs of patients with primary brain tumours and the provision of a health and well-being event.

      Emerson, Julie; Robson, Sara; Molloy, Liz; Smith, Charlotte; McBain, Catherine A; Christie Hospital NHS Foundation Trust, Manchester (2017)