• 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)
    • 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.
    • 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)
    • Why young women gain weight: A narrative review of influencing factors and possible solutions

      Pegington, Mary; French, DP; Harvie, Michelle N; Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK (2020)
      Significant weight gain occurs in women during young adulthood, which increases risk of diseases such as diabetes, cardiovascular disease, and many cancers. This review aims to inform future individually targeted weight gain prevention programmes and summarizes possible targets: key life events, mediators that influence energy intake and physical activity levels, and moderators that could identify groups of women at greatest risk. Life events affecting weight include pregnancy and motherhood, smoking cessation, marriage and cohabiting, attending university, and possibly bereavement. Research has identified successful methods for preventing weight gain associated with pregnancy and motherhood, which could now be used in practice, but evidence is inconclusive for preventing weight gain around other life events. Weight gain is mediated by lack of knowledge and skills around food and nutrition, depression, anxiety, stress, satiety, neural responses, and possibly sleep patterns and premenstrual cravings. A paucity of research exists into altering these to limit weight gain. Moderators include socioeconomic status, genetics, personality traits, and eating styles. More research is required to identify at-risk females and engage them in weight gain prevention. There is a need to address evidence gaps highlighted and implement what is currently known to develop effective strategies to limit weight gain in young women.
    • Widespread and functional RNA circularization in localized prostate cancer

      Chen, S; Huang, V; Xu, X; Livingstone, J; Soares, F; Jeon, J; Zeng, Y; Hua, JT; Petricca, J; Guo, H; et al. (2019)
      The cancer transcriptome is remarkably complex, including low-abundance transcripts, many not polyadenylated. To fully characterize the transcriptome of localized prostate cancer, we performed ultra-deep total RNA-seq on 144 tumors with rich clinical annotation. This revealed a linear transcriptomic subtype associated with the aggressive intraductal carcinoma sub-histology and a fusion profile that differentiates localized from metastatic disease. Analysis of back-splicing events showed widespread RNA circularization, with the average tumor expressing 7,232 circular RNAs (circRNAs). The degree of circRNA production was correlated to disease progression in multiple patient cohorts. Loss-of-function screening identified 11.3% of highly abundant circRNAs as essential for cell proliferation; for ?90% of these, their parental linear transcripts were not essential. Individual circRNAs can have distinct functions, with circCSNK1G3 promoting cell growth by interacting with miR-181. These data advocate for adoption of ultra-deep RNA-seq without poly-A selection to interrogate both linear and circular transcriptomes.
    • Widespread regular sunscreen application deemed not useful in the U.S.A.: reply from authors.

      Olsen, C M; Green, Adèle C; Whiteman, D C; QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD, 4006, Australia (2018-06-07)
    • Will cervical screening remain cost-effective in women offered the next generation nonavalent HPV vaccine? Results for four developed countries.

      Simms, K; Smith, M; Lew, J; Kitchener, Henry C; Castle, P; Canfell, K; Cancer Research Division, Cancer Council NSW, 153 Dowling Street, Woolloomooloo, Sydney, NSW, 2011, Australia (2016-08-19)
      A next generation nonavalent human papillomavirus (HPV) vaccine ('HPV9 vaccine') is being introduced in several countries. The aims of this study were to evaluate whether cervical screening will remain cost-effective in cohorts offered nonavalent vaccines and if so, to characterize the optimal number of screening tests. We used a dynamic model of HPV vaccination and cervical screening to evaluate the cost-effectiveness of strategies involving varying numbers of primary HPV tests per lifetime for cohorts offered the nonavalent vaccine as 12 year-olds. For each of four countries - the USA, New Zealand (NZ), Australia and England - we considered local factors including vaccine uptake rates (USA/NZ uptake ∼50%; Australia/England uptake >70%); attributable fractions of HPV9-included types; demographic factors, costs and indicative willingness-to-pay (WTP) thresholds. Extensive sensitivity analysis was performed. We found that, in the USA, four screens per lifetime was the most likely scenario, with a 34% probability of being optimal at WTP US$50,000/LYS, increasing to 84% probability US$100,000/LYS. In New Zealand, five screens per lifetime was the most likely scenario, with 100% probability of being optimal at NZ$42,000/LYS. In Australia, two screens per lifetime was the most likely scenario, with 62% probability of being optimal at AU$50,000/LYS. In England, four screens per lifetime was the most likely scenario, with 32% probability of being optimal at WTP of GB£20,000/QALY, increasing to 92% probability at GB£30,000/QALY. We conclude that some cervical screening will remain cost-effective, even in countries with high vaccination coverage. However, the optimal number of screens may vary between countries. This article is protected by copyright. All rights reserved.
    • Wiskott-Aldrich syndrome protein (WASP) is a tumor suppressor in T cell lymphoma.

      Menotti, Matteo; Ambrogio, C; Cheong, TC; Pighi, C; Mota, I; Cassel, SH; Compagno, M; Wang, Q; Dall'Olio, R; Minero, VG; et al. (2018)
      In T lymphocytes, the Wiskott-Aldrich Syndrome protein (WASP) and WASP-interacting-protein (WIP) regulate T cell antigen receptor (TCR) signaling, but their role in lymphoma is largely unknown. Here we show that the expression of WASP and WIP is frequently low or absent in anaplastic large cell lymphoma (ALCL) compared to other T cell lymphomas. In anaplastic lymphoma kinase-positive (ALK+) ALCL, WASP and WIP expression is regulated by ALK oncogenic activity via its downstream mediators STAT3 and C/EBP-?. ALK+ lymphomas were accelerated in WASP- and WIP-deficient mice. In the absence of WASP, active GTP-bound CDC42 was increased and the genetic deletion of one CDC42 allele was sufficient to impair lymphoma growth. WASP-deficient lymphoma showed increased mitogen-activated protein kinase (MAPK) pathway activation that could be exploited as a therapeutic vulnerability. Our findings demonstrate that WASP and WIP are tumor suppressors in T cell lymphoma and suggest that MAP-kinase kinase (MEK) inhibitors combined with ALK inhibitors could achieve a more potent therapeutic effect in ALK+ ALCL.