• Visualization of the nucleus and nuclear envelope in situ by SEM in tissue culture cells.

      Allen, Terence D; Rutherford, Sandra A; Murray, Stephen M; Gardiner, Fiona; Kiseleva, Elena; Goldberg, Martin W; Drummond, Sheona P; Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, Withington, Manchester M20 4BX, UK. tallen@picr.man.ac.uk (2007)
      Our previous work characterizing the biogenesis and structural integrity of the nuclear envelope and nuclear pore complexes (NPCs) has been based on amphibian material but has recently progressed into the analysis of tissue-culture cells. This protocol describes methods for the high resolution visualization, by field-emission scanning electron microscopy (FESEM), of the nucleus and associated structures in tissue culture cells. Imaging by fluorescence light microscopy shows general nuclear and NPC information at a resolution of approximately 200 nm, in contrast to the 3-5 nm resolution provided by FESEM or transmission electron microscopy (TEM), which generates detail at the macromolecular level. The protocols described here are applicable to all tissue culture cell lines tested to date (HeLa, A6, DLD, XTC and NIH 3T3). The processed cells can be stored long term under vacuum. The protocol can be completed in 5 d, including 3 d for cell growth, 1 d for processing and 1 d for imaging.
    • Vitamin C and Doxycycline: a synthetic lethal combination therapy targeting metabolic flexibility in cancer stem cells (CSCs).

      De Francesco, Ernestina M; Bonuccelli, G; Maggiolini, M; Sotgia, F; Lisanti, M; Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy (2017-06-09)
      Here, we developed a new synthetic lethal strategy for further optimizing the eradication of cancer stem cells (CSCs). Briefly, we show that chronic treatment with the FDA-approved antibiotic Doxycycline effectively reduces cellular respiration, by targeting mitochondrial protein translation. The expression of four mitochondrial DNA encoded proteins (MT-ND3, MT-CO2, MT-ATP6 and MT-ATP8) is suppressed, by up to 35-fold. This high selection pressure metabolically synchronizes the surviving cancer cell sub-population towards a predominantly glycolytic phenotype, resulting in metabolic inflexibility. We directly validated this Doxycycline-induced glycolytic phenotype, by using metabolic flux analysis and label-free unbiased proteomics.Next, we identified two natural products (Vitamin C and Berberine) and six clinically-approved drugs, for metabolically targeting the Doxycycline-resistant CSC population (Atovaquone, Irinotecan, Sorafenib, Niclosamide, Chloroquine, and Stiripentol). This new combination strategy allows for the more efficacious eradication of CSCs with Doxycycline, and provides a simple pragmatic solution to the possible development of Doxycycline-resistance in cancer cells. In summary, we propose the combined use of i) Doxycycline (Hit-1: targeting mitochondria) and ii) Vitamin C (Hit-2: targeting glycolysis), which represents a new synthetic-lethal metabolic strategy for eradicating CSCs.This type of metabolic Achilles' heel will allow us and others to more effectively "starve" the CSC population.
    • Vitamin D Pathway Gene Polymorphisms and Keratinocyte Cancers: A Nested Case-Control Study and Meta-Analysis.

      Von Schuckmann, L; Law, M; Montgomery, G; Green, Adèle C; Van der Pols, J; The University of Queensland, School of Public Health, Herston, Australia (2016-05)
      The vitamin D endocrine system is implicated in skin carcinogenesis and polymorphisms in genes associated with the vitamin D receptor (VDR) gene may alter the risk of keratinocyte cancers (basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)).
    • Waif1/5T4 inhibits Wnt/β-catenin signaling and activates noncanonical Wnt pathways by modifying LRP6 subcellular localization.

      Kagermeier-Schenk, B; Wehner, D; Ozhan-Kizil, G; Yamamoto, H; Li, J; Kirchner, K; Hoffmann, C; Stern, Peter L; Kikuchi, A; Schambony, A; et al. (2011-12-13)
      Wnt proteins can activate distinct signaling pathways, but little is known about the mechanisms regulating pathway selection. Here we show that the metastasis-associated transmembrane protein Wnt-activated inhibitory factor 1 (Waif1/5T4) interferes with Wnt/β-catenin signaling and concomitantly activates noncanonical Wnt pathways. Waif1 inhibits β-catenin signaling in zebrafish and Xenopus embryos as well as in mammalian cells, and zebrafish waif1a acts as a direct feedback inhibitor of wnt8-mediated mesoderm and neuroectoderm patterning during zebrafish gastrulation. Waif1a binds to the Wnt coreceptor LRP6 and inhibits Wnt-induced LRP6 internalization into endocytic vesicles, a process that is required for pathway activation. Thus, Waif1a modifies Wnt/β-catenin signaling by regulating LRP6 subcellular localization. In addition, Waif1a enhances β-catenin-independent Wnt signaling in zebrafish embryos and Xenopus explants by promoting a noncanonical function of Dickkopf1. These results suggest that Waif1 modulates pathway selection in Wnt-receiving cells.
    • WDR5 modulates cell motility and morphology and controls nuclear changes induced by a 3D environment.

      Wang, Pengbo; Dreger, M; Madrazo, E; Williams, C; Samaniego, R; Hodson, N; Monroy, F; Baena, Esther; Sánchez-Mateos, P; Hurlstone, A; et al. (2018-07-09)
      Cell migration through extracellular matrices requires nuclear deformation, which depends on nuclear stiffness. In turn, chromatin structure contributes to nuclear stiffness, but the mechanosensing pathways regulating chromatin during cell migration remain unclear. Here, we demonstrate that WD repeat domain 5 (WDR5), an essential component of H3K4 methyltransferase complexes, regulates cell polarity, nuclear deformability, and migration of lymphocytes in vitro and in vivo, independent of transcriptional activity, suggesting nongenomic functions for WDR5. Similarly, depletion of RbBP5 (another H3K4 methyltransferase subunit) promotes similar defects. We reveal that a 3D environment increases the H3K4 methylation dependent on WDR5 and results in a globally less compacted chromatin conformation. Further, using atomic force microscopy, nuclear particle tracking, and nuclear swelling experiments, we detect changes in nuclear mechanics that accompany the epigenetic changes induced in 3D conditions. Indeed, nuclei from cells in 3D environments were softer, and thereby more deformable, compared with cells in suspension or cultured in 2D conditions, again dependent on WDR5. Dissecting the underlying mechanism, we determined that actomyosin contractility, through the phosphorylation of myosin by MLCK (myosin light chain kinase), controls the interaction of WDR5 with other components of the methyltransferase complex, which in turn up-regulates H3K4 methylation activation in 3D conditions. Taken together, our findings reveal a nongenomic function for WDR5 in regulating H3K4 methylation induced by 3D environments, physical properties of the nucleus, cell polarity, and cell migratory capacity.
    • Weekly platinum chemotherapy for recurrent ovarian cancer.

      Clamp, Andrew R; Jayson, Gordon C (2002-01-07)
    • Welcome to Tumour Virus Research

      Stern, Peter L; Banks, L.; Manchester Cancer Research Centre, University of Manchester, Manchester, M20 4G (2021)
    • What are mast cells for?

      Dexter, T Michael; Stoddart, R; Quazzaz, S; Department of Experimental Haematology, Christie Hospital and Holt Radium Institute, Manchester. (1981-05-14)
    • What Do the Guidelines Say for Metastatic Prostate Cancer Starting Androgen Deprivation Therapy? National Comprehensive Cancer Network, European Society for Medical Oncology, and European Association of Urology recommendations

      Yu, EY; Gillessen, Silke; Mottet, N; Department of Medicine, Division of Oncology, University of Washington, Seattle, WA, USA; (2018)
      Clinical trial data forms the foundation of how we treat men with metastatic prostate cancer who are initiating therapy. However, clinical trial data does not answer everything; hence, good clinical practice, pragmatism, and occasionally extrapolation drives how we manage these patients. Fortunately, multiple international guideline committees meet regularly and offer clinical guidance. In this mini-review, we focus on the United States National Comprehensive Cancer Network, European Society for Medical Oncology, and European Association of Urology (EAU) recommendations for the initial treatment of metastatic prostate cancer.
    • What is an apoptotic index measuring? A commentary.

      Potten, Christopher S; Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, UK. (1996-12)
    • What is apoptosis, and why is it important?

      Renehan, Andrew G; Booth, Catherine; Potten, Christopher S; Cancer Research Campaign Department of Epithelial Biology, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, UK. arenehan@picr.man.ac.uk (2001-06-23)
    • What's new in the management of cutaneous T-cell lymphoma?

      McFarlane, V; Friedmann, P S; Illidge, Timothy M; Southampton Oncology Centre, Southampton University NHS Trust, Southampton S016 6YD, UK. (2005-05)
      The aetiology and clinical management of primary cutaneous T-cell lymphoma (CTCL) and specifically of mycosis fungoides and Sezary syndrome are poorly defined. Interesting new insights into CTCL disease biology as well as a number of emerging of novel therapeutic interventions make this an increasingly interesting area for dermatologists and oncologists involved in the treatment of CTCL. This review article covers much of this new information including new drugs, such as denileukin diftitox (Ontak) a targeted cytotoxic biological agent, Bexarotene an RXR selective retinoid, anti-CD4 monoclonal antibodies (mAb), new cytotoxics agents and vaccines.
    • When what you see is not always what you get: raising the bar of evidence for new diagnostic imaging modalities

      Sundahl, N.; Gillessen, Silke; Sweeney, C.; Ost, P.; Department of Radiation Oncology, Ghent University Hospital, Ghent, Belgium; Division of Radiotherapy and Imaging, Institute of Cancer Research, London, UK. Electronic address: nora.sundahl@ugent.be. (2020)
      Even though prostate-specific membrane antigen (PSMA)-positron emission tomography (PET)-computed tomography (CT) is more accurate than conventional imaging in prostate cancer patients, its impact on patient-relevant outcomes is unknown. We argue that more evidence is required before using PSMA-PET-CT as the standard of care for staging.
    • Where do selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) now fit into breast cancer treatment algorithms?

      Howell, Anthony; Howell, Sacha J; Clarke, Robert B; Anderson, Elizabeth; CRC Department of Medical Oncology, Christie Hospital NHS Trust, M20 4BX, Manchester, UK. maria.parker@christie-tr.nwest.nhs.uk (2001-12)
      The agents used for endocrine therapy in patients with breast cancer have changed markedly over the past decade. Tamoxifen remains the anti-oestrogen of choice, but could be replaced by the oestrogen receptor down-regulator ICI 182780 or by the fixed ring triphenylethylene arzoxifene (previously SERM III) soon. Whilst aminoglutethimide and 4-OH androstenedione were the aromatase inhibitors of choice, they have been replaced by non-steroidal (anastrozole and letrozole) and steroidal (exemestane) inhibitors of high potency and low side effect profile. Previously, often used treatments such as progestogens (megestrol acetate and medroxyprogesterone acetate) and androgens are now rarely used or confined to fourth or fifth line treatments. The LHRH agonist, goserelin, remains the treatment of choice for pre-menopausal patients with advanced breast cancer although recent randomised trials indicate a response, time to progression and survival advantage for the combination of goserelin and tamoxifen compared with goserelin alone.The newer treatments have led to questions concerning the optimum sequence of agents to use in advanced breast cancer and as neo-adjuvant and adjuvant therapy in relation to surgery. Two trials of anastrozole compared with tamoxifen and one trial of letrozole compared with tamoxifen indicate that the new triazole aromatase inhibitors have a significant advantage over the anti-oestrogen with respect to time to progression and survival. Similarly, triazole aromatase inhibitors give faster and more complete responses compared with tamoxifen when used in post-menopausal women before surgery.Major research questions remain with respect to the aromatase inhibitors used as adjuvant therapy. Anastrozole is being tested alone or in combination with tamoxifen compared with tamoxifen in the 'so-called' ATAC trial. Over 9000 patients have been randomised to this important study: the results will be available late-2001. A similar study comparing letrozole and tamoxifen started recently under the auspices of the Breast International Group. Importantly, this trial is also comparing the sequence of tamoxifen followed by letrozole (or vice versa). A similar trial of exemestane given after 2-3 years of tamoxifen compared with 5 years of tamoxifen is recruiting well as is a study comparing letrozole (or placebo) for 5 years after 5 years of adjuvant tamoxifen. These studies may show that aromatase inhibitors are superior to tamoxifen or that a sequence is preferable.ICI 182780 causes complete oestrogen receptor down-regulation leading to a the lack of agonist activity of the drug. Two trials of ICI 182780 compared with anastrozole for advanced disease will report later this year and a comparison with tamoxifen next year. Arzoxifene (SERM III) is being tested against tamoxifen. These studies are likely to result in new anti-oestrogens being introduced into the clinic.Most of our endocrine treatments deprived the tumour cell of oestradiol. In vitro experiments with MCF-7 cells indicate that tumour cells can adapt and then grow in response to low oestrogen concentrations in the tissue--culture medium. Importantly, the cells were shown to apoptose in response to high oestrogen concentrations. A recent clinical trial has demonstrated a high response rate to stilboestrol given after a median of four previous oestrogen depriving endocrine therapies. These data and the newer treatments available indicate a need to re-think our general approach to endocrine therapy and endocrine prevention.
    • Which are the hematopoietic stem cells? [or: don't debunk the history!]

      Lord, Brian I; Dexter, T Michael; CRC Department of Experimental Haematology, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, UK. (1995-11)
    • Which are the leukaemic cells?

      Lajtha, L G; Paterson Laboratories, CHristie Hospital and Holt Radium Institute, Withington, Manchester, M20 9BX, UK (1981)
      Two features are known about acute myeloid leukaemia in man: (1) the long time-scale from identifiable leukaemogenic stimulus and onset of the clinical disease and (2) the successful induction and duration of long clinical remission. These indicate three probabilities: First, that the target cell for leukaemogenetic insult (in AML) is the pluripotent stem cell; second, that the leukaemic stem line is a small minority population within the total leukaemic cell mass; third, when the leukaemic stem line is not greatly exceeding the normal stem cell numbers, its proliferation may be still under partial control.
    • WHO/ILO work-related burden of disease and injury: protocol for systematic reviews of occupational exposure to solar ultraviolet radiation and of the effect of occupational exposure to solar ultraviolet radiation on melanoma and non-melanoma skin cancer

      Paulo, MS; Adam, B; Akagwu, C; Akparibo, I; Al-Rifai, RH; Bazrafshan, S; Gobba, F; Green, Adèle C; Ivanov, I; Kezic, S; et al. (2019)
      BACKGROUND: The World Health Organization (WHO) and the International Labour Organization (ILO) are developing a joint methodology for estimating the national and global work-related burden of disease and injury (WHO/ILO joint methodology), with contributions from a large network of experts. In this paper, we present the protocol for two systematic reviews of parameters for estimating the number of deaths and disability-adjusted life years from melanoma and non-melanoma skin cancer (or keratinocyte carcinoma) from occupational exposure to solar ultraviolet radiation, to inform the development of the WHO/ILO joint methodology. OBJECTIVES: We aim to systematically review studies on occupational exposure to solar ultraviolet radiation (Systematic Review 1) and systematically review and meta-analyse estimates of the effect of occupational exposure to solar ultraviolet radiation on melanoma and non-melanoma skin cancer (Systematic Review 2), applying the Navigation Guide systematic review methodology as an organizing framework and conducting both systematic reviews in tandem and in a harmonized way. DATA SOURCES: Separately for Systematic Reviews 1 and 2, we will search electronic academic databases for potentially relevant records from published and unpublished studies, including Ovid Medline, PubMed, EMBASE, and Web of Science. We will also search electronic grey literature databases, Internet search engines and organizational websites; hand-search reference list of previous systematic reviews and included study records and consult additional experts. STUDY ELIGIBILITY AND CRITERIA: We will include working-age (?15?years) workers in the formal and informal economy in any WHO and/or ILO Member State, but exclude children (<15?years) and unpaid domestic workers. For Systematic Review 1, we will include quantitative studies on the prevalence of relevant levels of occupational exposure to solar ultraviolet radiation (i.e. <0.33?SED/d and ?0.33?SED/d) and of the total working time spent outdoors, stratified by country, sex, age and industrial sector or occupation, in the years 1960 to 2018. For Systematic Review 2, we will include randomized controlled trials, cohort studies, case-control studies and other non-randomized intervention studies with an estimate of the effect of any occupational exposure to solar ultraviolet radiation (i.e., ?0.33?SED/d) on the prevalence of, incidence of or mortality due to melanoma and non-melanoma skin cancer, compared with the theoretical minimum risk exposure level (i.e. <0.33?SED/d). STUDY APPRAISAL AND SYNTHESIS METHODS: At least two review authors will independently screen titles and abstracts against the eligibility criteria at a first stage and full texts of potentially eligible records at a second stage, followed by extraction of data from qualifying studies. At least two review authors will assess the risk of bias and the quality of evidence, using the most suited tools currently available. For Systematic Review 2, if feasible, we will combine relative risks using meta-analysis. We will report results using the guidelines for accurate and transparent health estimates reporting (GATHER) for Systematic Review 1 and the preferred reporting items for systematic reviews and meta-analyses guidelines (PRISMA) for Systematic Review 2. PROSPERO REGISTRATION NUMBER: CRD42018094817.
    • Wholesomeness and safety of irradiated foods.

      Swallow, A John; Cancer Research Campaign Department of Biophysical Chemistry, Patterson Institute for Cancer Research, Christie Hospital & Holt Radium Institute, Manchester, England. (1991)
      Irradiation with gamma-rays, X-rays or fast electrons can be used to change foodstuffs in beneficial ways or to destroy harmful organisms. Gamma rays do not induce radioactivity in foods, but X-rays and fast electrons can induce short lived radioactivity if sufficiently energetic. This imposes limitations on the energies which can be used, and a short wait between irradiation and consumption may be advisable. Irradiation produces chemical changes in foodstuffs, and some foods are unsuitable for irradiation. With appropriate foods, trials with animals and human volunteers generally show that the product is safe. Some loss in nutritional quality can take place, which could be significant for some individuals, but are unlikely to be important for those on a balanced diet. Irradiation does not eliminate all risk from microbial contamination. Foods to be irradiated should be good quality, and need to be kept under proper conditions after irradiation. Irradiated foods should be appropriately labelled. Tests for radiation would help to enforce necessary controls. If the process is properly carried out on appropriate foods, and all due precautions are taken, irradiated foods are wholesome and safe.
    • Why do young women gain weight? A review of influencing factors and possible solutions

      Pegington, Mary; French, DP; Harvie, Michelle N; Division of Cancer Services, Faculty of Biology, Medicine and Health, University of Manchester, Manchester (2020)