• Building better chimeric antigen receptors for adoptive T cell therapy.

      Bridgeman, John S; Hawkins, Robert E; Hombach, Andreas A; Abken, Hinrich; Gilham, David E; Cellular Therapy Group, Cancer Research UK Department of Medical Oncology, Paterson Institute for Cancer Research, Manchester, UK. (2010-04)
      The last few years have seen the transfer of two decades of research into Chimeric Antigen Receptors (CARs) into clinical trials. Despite this extensive research, there is still a great deal of debate into the optimal design strategy for these, primarily, anti-cancer entities. The archetypal CAR consists of a single-chain antibody fragment, specific to a tumour-associated antigen, fused to a component of the T-cell receptor complex (typically CD3zeta) which on antigen binding primes the engrafted T-cell for anti-tumour activity. The modular nature of these artificial receptors has enabled researchers to modify aspects of their structure, including the extracellular spacer, transmembrane and cytoplasmic domain, to achieve laboratory defined optimal activity. Despite this there is no consensus on the optimal structure, a problem exacerbated by conflicting results using identical receptors. In this review, we provide a structural overview of CAR development and highlight areas that require further refinement. We also attempt to identify possible reasons for conflicting results in the hope that this information will inspire future rational design strategies for optimal tumour targeting using CARs.
    • Burkitt Lymphoma International Prognostic Index

      Olszewski, A. J.; Jakobsen, L. H.; Collins, G. P.; Cwynarski, K.; Bachanova, V.; Blum, K. A.; Boughan, K. M.; Bower, M.; Dalla Pria, A.; Danilov, A.; et al. (2021)
      Purpose: Burkitt lymphoma (BL) has unique biology and clinical course but lacks a standardized prognostic model. We developed and validated a novel prognostic index specific for BL to aid risk stratification, interpretation of clinical trials, and targeted development of novel treatment approaches. Methods: We derived the BL International Prognostic Index (BL-IPI) from a real-world data set of adult patients with BL treated with immunochemotherapy in the United States between 2009 and 2018, identifying candidate variables that showed the strongest prognostic association with progression-free survival (PFS). The index was validated in an external data set of patients treated in Europe, Canada, and Australia between 2004 and 2019. Results: In the derivation cohort of 633 patients with BL, age ≥ 40 years, performance status ≥ 2, serum lactate dehydrogenase > 3× upper limit of normal, and CNS involvement were selected as equally weighted factors with an independent prognostic value. The resulting BL-IPI identified groups with low (zero risk factors, 18% of patients), intermediate (one factor, 36% of patients), and high risk (≥ 2 factors, 46% of patients) with 3-year PFS estimates of 92%, 72%, and 53%, respectively, and 3-year overall survival estimates of 96%, 76%, and 59%, respectively. The index discriminated outcomes regardless of HIV status, stage, or first-line chemotherapy regimen. Patient characteristics, relative size of the BL-IPI groupings, and outcome discrimination were consistent in the validation cohort of 457 patients, with 3-year PFS estimates of 96%, 82%, and 63% for low-, intermediate-, and high-risk BL-IPI, respectively. Conclusion: The BL-IPI provides robust discrimination of survival in adult BL, suitable for use as prognostication and stratification in trials. The high-risk group has suboptimal outcomes with standard therapy and should be considered for innovative treatment approaches.
    • C-H Borylation: no need to stop for directions

      Osborne, Hugh C; Durie, A.; Schmidt, Christine K; Larrosa, I.; Department of Chemistry, School of Natural Sciences, University of Manchester, Oxford Road, Manchester M13 9PL, (2020)
      A recent work by Hartwig et al. details an efficient method to borylate strong primary C(sp3)–H bonds via iridium-catalysed C–H activation. The conditions confer counterintuitive selectivity over more labile C–H bonds, while providing an avenue for a gamut of synthetically valuable late-stage functionalisations through versatile borylate intermediates.
    • c-kit receptors in ovarian tumors and the response of ovarian carcinoma cell lines ro recombinant human stem cell factor

      Wrigley, E; McGown, Alan T; Ward, Timothy H; Ewen, C; Crowther, Derek; Department of Medical Oncology, Christie Hospital; (1996)
    • C-kit receptors in ovarian tumors and the response of ovarian carcinoma cell lines to recombinant human stem cell factor.

      Wrigley, E; McGown, Alan T; Ward, Timothy H; Ewen, C; Crowther, Derek; Christie Hospital, Wilmslow Road, Manchester, M20 4BX (1996)
    • C-terminally truncated human O6-alkylguanine-DNA alkyltransferase retains activity.

      Elder, Rhoderick H; Tumelty, J; Douglas, K T; Margison, Geoffrey P; Rafferty, Joseph A; CRC Department of Carcinogenesis, Paterson Institute for Cancer Research, Christie Hospital (NHS) Trust, Manchester, U.K. (1992-08-01)
      A cDNA encoding the human O6-alkylguanine-DNA alkyltransferase (ATase; EC 2.1.1.63; methylated-DNA: protein-cysteine methyltransferase) has been manipulated to generate a C-terminally deleted protein which retains full methyl-transfer activity. The elimination of 22 amino-acid residues from the C-terminus was achieved by endonuclease-SacI digestion of the 623 bp cDNA coding sequence and ligation of a SacI/HindIII linker containing an in-frame stop codon. The truncated protein was characterized by its reduced molecular mass in immunoblots probed with an antiserum against the full-length protein and by fluorography after incubation with [3H]methylated calf thymus DNA. The rate of methyl transfer was virtually identical for the full-length and truncated ATases. The construction of such a truncated, yet still functional, ATase, with a molecular mass of 19.7 kDa should facilitate a detailed n.m.r. structural study and help to determine the functional significance of the C-terminal domain of mammalian ATases.
    • The C/EBPdelta protein is stabilized by estrogen receptor α activity, inhibits SNAI2 expression and associates with good prognosis in breast cancer.

      Mendoza-Villanueva, D; Balamurugan, K; Ali, H; Kim, S; Sharan, S; Johnson, R; Merchant, A; Caldas, C; Landberg, Göran; Sterneck, E; et al. (2016-05-16)
      Hypoxia and inflammatory cytokines like interleukin-6 (IL-6, IL6) are strongly linked to cancer progression, and signal in part through the transcription factor Ccaat/enhancer-binding protein δ (C/EBPδ, CEBPD), which has been shown to promote mesenchymal features and malignant progression of glioblastoma. Here we report a different role for C/EBPδ in breast cancer. We found that the C/EBPδ protein is expressed in normal breast epithelial cells and in low-grade cancers. C/EBPδ protein (but not mRNA) expression correlates with estrogen receptor (ER+) and progesterone receptor (PGR) expression and longer progression-free survival of breast cancer patients. Specifically in ER+ breast cancers, CEBPD-but not the related CEBPB-mRNA in combination with IL6 correlated with lower risk of progression. Functional studies in cell lines showed that ERα promotes C/EBPδ expression at the level of protein stability by inhibition of the FBXW7 pathway. Furthermore, we found that C/EBPδ attenuates cell growth, motility and invasiveness by inhibiting expression of the SNAI2 (Slug) transcriptional repressor, which leads to expression of the cyclin-dependent kinase inhibitor CDKN1A (p21(CIP1/WAF1)). These findings identify a molecular mechanism by which ERα signaling reduces the aggressiveness of cancer cells, and demonstrate that C/EBPδ can have different functions in different types of cancer. Furthermore, our results support a potentially beneficial role for the IL-6 pathway specifically in ER+ breast cancer and call for further evaluation of the role of intra-tumoral IL-6 expression and of which cancers might benefit from current attempts to target the IL-6 pathway as a therapeutic strategy.Oncogene advance online publication, 16 May 2016; doi:10.1038/onc.2016.156.
    • C1q binding activity in the sera of patients with chronic lung diseases.

      Cooper, K Michael; Moore, Michael; Hilton, A M; Paterson Laboratories, Christie Hospital and Holt Radium Institute, Manchester, UK (1981-07)
      Sera from patients with chronic lung diseases were tested for the presence of immune complexes (ICs) by the 125I-C1q-binding assay. Contrary to earlier reports, modification of the test system by addition of heparin decreased rather than increased the ability of the test to discriminate between control and pathological sera. Using the unmodified system, elevated C1q-binding activity (C1qBA) was found in patients with asthma (18%), chronic bronchitis (18%), sarcoidosis (18%), fibrosing alveolitis (50%), bronchogenic carcinoma (52%) and bronchiectasis (67%). Studies with the reducing agent 2-mercaptoethanol (2-ME) suggested a role for IgM rheumatoid factor (RF) and/or IgG-containing complexes in the C1q-reactive material of sera from patients with bronchiectasis and bronchogenic carcinoma. In the latter two groups, C1qBA was found to correlate with serum levels of IgG and IgA but not with C3 and C4. A weak condition between levels of C-reactive protein (CRP) and C1qBA was found in the bronchogenic carcinoma group. Carcinoembryonic antigen (CEA) levels were elevated in all groups studied but no correlation with C1qBA was demonstrated, suggesting that CEA and CEA-ICs, if present, do not have an influence on the C1qBA of such sera. The results indicate that elevated serum C1qBA is a concomitant of both chronic inflammatory and neoplastic diseases of the lung but the extent of any similarity in the non-immunoglobulin components of the immune complexes in the respective conditions remains unknown.
    • CADRE: the Central Aspergillus Data REpository.

      Mabey, J E; Anderson, M J; Giles, P F; Miller, Crispin J; Attwood, Teresa K; Paton, N W; Bornberg-Bauer, E; Robson, G D; Oliver, S; Denning, David W; et al. (2004-01-01)
      CADRE is a public resource for housing and analysing genomic data extracted from species of Aspergillus. It arose to enable maintenance of the complete annotated genomic sequence of Aspergillus fumigatus and to provide tools for searching, analysing and visualizing features of fungal genomes. By implementing CADRE using Ensembl, a framework is in place for storing and comparing several genomes: the resource will thus expand by including other Aspergillus genomes (such as Aspergillus nidulans) as they become available. CADRE is accessible at http://www.cadre. man.ac.uk.
    • Calcium signatures are decoded by plants to give specific gene responses.

      Whalley, Helen J; Knight, M; Cell Signalling Group, Paterson Institute for Cancer Research, The University of Manchester, Wilmslow Road, Manchester, M20 4BX, UK. (2013-02)
    • Calibration of low activity caesium tubes and needles traceable to the therapy level standard.

      Deshpande, N A; Wilkinson, John M; North Western Medical Physics Department, Christie Hospital, Manchester, UK. (1994-02)
      A technique for deriving the reference air kerma rate for low activity brachytherapy sources that is traceable to the therapy level standard at the National Physical Laboratory is presented. Correction factors have been generated to account for the finite source and detector size. The air kerma rate calibration of the secondary standard for caesium quality has been derived by polynomial curve fitting. The reference air kerma rates for several caesium tubes and needles have been determined and the results compared with the manufacturers' source test reports. For all the source types used the agreement between methods was within 2%.
    • A call to standardise the BCC:SCC ratio

      Jiyad, Z.; Marquart, L.; Green, Adèle C; Dermatology Unit, St George's University of London, London, UK. (2020)
      Basal cell carcinoma (BCC) followed by squamous cell carcinoma (SCC) are the two commonest cancers in white populations worldwide.1 While sharing some features, they are distinct clinically and pathologically and thus the ratio of BCC to SCC incidence rates serves as a useful composite that enables immediate comparisons of trends within and between populations. There is a widely held belief that the BCC:SCC ratio sits relatively constantly at around 4:1 in the general population, though this belief has little apparent basis.
    • Can biological markers improve the management of breast cancer patients? Biomarkers Ad-hoc Group of the United Kingdom Coordinating Committee on Cancer Research.

      Leake, Robin; Anderson, Elizabeth; Dowsett, Mitch; Iles, Ray; Nicholson, Robert I; Robertson, John F R; Walker, Rosemary (2000-05)
    • Can metabolomics in addition to genomics add to prognostic and predictive information in breast cancer?

      Howell, Anthony; School of Cancer and Enabling Studies, University of Manchester, Paterson Institute for Cancer Research, Manchester, UK. anthony.howell@christie.nhs.uk (2010)
      Genomic data from breast cancers provide additional prognostic and predictive information that is beginning to be used for patient management. The question arises whether additional information derived from other 'omic' approaches such as metabolomics can provide additional information. In an article published this month in BMC Cancer, Borgan et al. add metabolomic information to genomic measures in breast tumours and demonstrate, for the first time, that it may be possible to further define subgroups of patients which could be of value clinically. See research article: http://www.biomedcentral.com/1471-2407/10/628.
    • Can oral nonsteroidal antiinflammatory drugs play a role in the prevention of basal cell carcinoma? A systematic review and metaanalysis.

      Muranushi, C; Olsen, C; Green, Adèle C; Pandeya, N; School of Population Health, University of Queensland, Brisbane, Australia (2015-09-30)
      Evidence for an association between aspirin or other nonsteroidal antiinflammatory drug (NSAID) use and basal cell carcinoma (BCC) has been inconsistent.
    • Can patient decision aids reduce decisional conflict in a de-escalation of breast radiotherapy clinical trial? The PRIMETIME Study Within a Trial implemented using a cluster stepped-wedge trial design

      Bhattacharya, I. S.; Haviland, J. S.; Turner, L.; Stobart, H.; Balasopoulou, A.; Stones, L.; Kirby, A. M.; Kirwan, Cliona C; Coles, C. E; Bliss, J. M.; et al. (2021)
      Background: For patients with early breast cancer considered at very-low risk of local relapse, risks of radiotherapy may outweigh the benefits. Decisions regarding treatment omission can lead to patient uncertainty (decisional conflict), which may be lessened with patient decision aids (PDA). PRIMETIME (ISRCTN 41579286) is a UK-led biomarker-directed study evaluating omission of adjuvant radiotherapy in breast cancer; an embedded Study Within A Trial (SWAT) investigated whether PDA reduces decisional conflict using a cluster stepped-wedge trial design. Methods: PDA diagrams and a video explaining risks and benefits of radiotherapy were developed in close collaboration between patient advocates and PRIMETIME trialists. The SWAT used a cluster stepped-wedge trial design, where each cluster represented the radiotherapy centre and referring peripheral centres. All clusters began in the standard information group (patient information and diagrams) and were randomised to cross-over to the enhanced information group (standard information plus video) at 2, 4 or 6 months. Primary endpoint was the decisional conflict scale (0-100, higher scores indicating greater conflict) which was assessed on an individual participant level. Multilevel mixed effects models used a random effect for cluster and a fixed effect for each step to adjust for calendar time and clustering. Robust standard errors were also adjusted for the clustering effect. Results: Five hundred twenty-one evaluable questionnaires were returned from 809 eligible patients (64%) in 24 clusters between April 2018 and October 2019. Mean decisional conflict scores in the standard group (N = 184) were 10.88 (SD 11.82) and 8.99 (SD 11.82) in the enhanced group (N = 337), with no statistically significant difference [mean difference - 1.78, 95%CI - 3.82-0.25, p = 0.09]. Compliance with patient information and diagrams was high in both groups although in the enhanced group only 121/337 (36%) reported watching the video. Conclusion: The low levels of decisional conflict in PRIMETIME are reassuring and may reflect the high-quality information provision, such that not everyone required the video. This reinforces the importance of working with patients as partners in clinical trials especially in the development of patient-centred information and decision aids.
    • Can the uptake of breast screening by Asian women be increased? A randomized controlled trial of a linkworker intervention.

      Hoare, Tanya; Thomas, C; Biggs, A; Booth, M; Bradley, S; Friedman, E; Centre for Cancer Epidemiology, Christie Hospital NHS Trust, Withington, Manchester. (1994-06)
      This study investigates the effectiveness of a linkworker intervention, giving encouragement and explanations about breast screening, on the subsequent attendance for screening by 'Asian' women. The control group received no visits. The study population comprised all women with Asian names, from a batch of general practices where high proportions of patients were Asian, who were invited for screening. It was found that 59 per cent of the intervention group could be contacted by linkworkers. No difference in attendance was found between the intervention and control groups (49 per cent and 47 per cent). Twenty-five per cent of women were permanently or temporarily not resident at the invitation address. Attendance for screening was related to length of stay in the United Kingdom. This type of intervention was not a successful strategy for promoting uptake by Asian women, and indicates that it is essential to evaluate rigorously projects with such objectives.
    • Cancer care benefits when people share their stories

      Heyworth, Ben; The Christie NHS FT, Manchester (2020)
    • A cancer cell-specific inducer of apoptosis.

      Green, Katie L; Brown, Craig; Roeder, Geraldine E; Southgate, Thomas D; Gaston, Kevin; Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, United Kingdom. (2007-06)
      Human papillomavirus (HPV) DNA is found in virtually all cervical cancers, strongly suggesting that these viruses are necessary to initiate this disease. The HPV E2 protein is required for viral replication, but E2 expression is usually lost in HPV-transformed cells because of the integration of viral DNA into the host chromosome. Several studies have shown that the reintroduction of E2 into HPV-transformed cells can induce growth arrest and apoptotic cell death. This raises the possibility that E2 could be useful in the treatment of HPV-induced disease. However, the effects of E2 on cell proliferation are not limited to HPV-transformed cells. The E2 protein from HPV type 16 can induce apoptosis via at least two pathways. One pathway involves the binding of E2 to p53 and operates in HPV-transformed cells, many non-HPV-transformed cell lines, and untransformed normal cells. The second pathway requires the binding of E2 to the viral genome and operates only in HPV-transformed cells. A mutation in E2 that significantly reduces the binding of this protein to p53 abrogates the induction of apoptosis in non-HPV-transformed cells and normal cells, but has no effect on the ability of the mutated protein to induce apoptosis in HPV-transformed cells. Here we show that a chimeric protein consisting of this mutant of E2, fused to the herpes simplex virus type 1 VP22 protein, can traffic between cells in a three-dimensional tumor model and induce apoptosis in HPV-transformed cells with high specificity. This cancer cell-specific inducer of apoptosis may be useful in the treatment of cervical cancer and other HPV-induced diseases.
    • Cancer chemotherapy: in vitro test.

      Fox, Brian W; Dexter, T Michael; Paterson Laboratories, Christie Hospital and Holt Radium Institute, Manchester (1978-07-27)