• The major human AP endonuclease (Ape1) is involved in the nucleotide incision repair pathway.

      Gros, Laurent; Ishchenko, Alexander A; Ide, Hiroshi; Elder, Rhoderick H; Saparbaev, Murat K; Groupe Réparation de l'ADN', UMR 8113 CNRS, LBPA-ENS Cachan, Institut Gustave Roussy, 39, rue Camille Desmoulins, 94805 Villejuif Cedex, France. (2004)
      In nucleotide incision repair (NIR), an endonuclease nicks oxidatively damaged DNA in a DNA glycosylase-independent manner, providing the correct ends for DNA synthesis coupled to the repair of the remaining 5'-dangling modified nucleotide. This mechanistic feature is distinct from DNA glycosylase-mediated base excision repair. Here we report that Ape1, the major apurinic/apyrimidinic endonuclease in human cells, is the damage- specific endonuclease involved in NIR. We show that Ape1 incises DNA containing 5,6-dihydro-2'-deoxyuridine, 5,6-dihydrothymidine, 5-hydroxy-2'-deoxyuridine, alpha-2'-deoxyadenosine and alpha-thymidine adducts, generating 3'-hydroxyl and 5'-phosphate termini. The kinetic constants indicate that Ape1-catalysed NIR activity is highly efficient. The substrate specificity and protein conformation of Ape1 is modulated by MgCl2 concentrations, thus providing conditions under which NIR becomes a major activity in cell-free extracts. While the N-terminal region of Ape1 is not required for AP endonuclease function, we show that it regulates the NIR activity. The physiological relevance of the mammalian NIR pathway is discussed.
    • Making connections at DNA replication forks: Mrc1 takes the lead.

      Labib, Karim; Cancer Research UK, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK. (2008-10-24)
      In a recent issue of Molecular Cell, Lou et al. (2008) demonstrate that the Mrc1 protein associates with the DNA polymerase that acts on the leading strand at replication forks, suggesting a potential mechanism that could help to preserve genome stability.
    • Making connections: p53 and the cathepsin proteases as co-regulators of cancer and apoptosis

      Soond, S. M.; Savvateeva, L. V.; Makarov, V. A.; Gorokhovets, N. V.; Townsend, Paul A; Zamyatnin, A. A., Jr.; Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Trubetskaya Str. 8-2, 119991 Moscow, Russia. (2020)
      While viewed as the "guardian of the genome", the importance of the tumor suppressor p53 protein has increasingly gained ever more recognition in modulating additional modes of action related to cell death. Slowly but surely, its importance has evolved from a mutated genetic locus heavily implicated in a wide array of cancer types to modulating lysosomal-mediated cell death either directly or indirectly through the transcriptional regulation of the key signal transduction pathway intermediates involved in this. As an important step in determining the fate of cells in response to cytotoxicity or during stress response, lysosomal-mediated cell death has also become strongly interwoven with the key components that give the lysosome functionality in the form of the cathepsin proteases. While a number of articles have been published highlighting the independent input of p53 or cathepsins to cellular homeostasis and disease progression, one key area that warrants further focus is the regulatory relationship that p53 and its isoforms share with such proteases in regulating lysosomal-mediated cell death. Herein, we review recent developments that have shaped this relationship and highlight key areas that need further exploration to aid novel therapeutic design and intervention strategies.
    • Male caregivers of patients with breast and gynecologic cancer: experiences from caring for their spouses and partners.

      Lopez, Violeta; Copp, Gina; Molassiotis, Alexander; Research Centre for Nursing and Midwifery Practice, Medical School, Australian National University, Canberra, Australia. violeta.lopez@anu.edu.au (2012)
      There is considerable evidence demonstrating the negative effects of caregiving particularly in the areas of psychological well-being and quality of life of family caregivers of patients with cancer. However, there is little work on male caregivers' subjective experience of caring for family members with cancer, and little is known on how caregivers experience the caring over time.
    • Malignant myelomonocytic cells after in vitro infection of marrow cells with Friend leukaemia virus.

      Testa, Nydia G; Dexter, T Michael; Scott, David; Teich, N M; Paterson Laboratories, Christie Hospital and Holt Radium Institute, Manchester (1980-01)
      Infection of long-term BDF1 marrow cultures with Friend leukaemia virus complex (FLV) induced transformed cells with myelomonocytic characteristics, which were isolated only 14 days after the viral infection. Criteria for transformation were growth in suspension cultures and high plating efficiency in agar. The lymphatic leukaemia virus (LLV) replicates in these suspension cultures, but the spleen focus-forming virus (SFFV) component of the FLV complex has not been detected. Injection of the transformed cells into syngeneic neonatal or adult mice leads to the development of leukaemia which can be demonstrated to be of donor origin by the presence of two metacentric marker chromosomes which are also seen in the cultured cells.
    • Malignant transformation and genetic alterations are uncoupled in early colorectal cancer progression

      Mamlouk, S.; Simon, T.; Tomás, L.; Wedge, David C; Arnold, A.; Menne, A.; Horst, D.; Capper, D.; Morkel, M.; Posada, D.; et al. (2020)
      Background: Colorectal cancer (CRC) development is generally accepted as a sequential process, with genetic mutations determining phenotypic tumor progression. However, matching genetic profiles with histological transition requires the analyses of temporal samples from the same patient at key stages of progression. Results: Here, we compared the genetic profiles of 34 early carcinomas with their respective adenomatous precursors to assess timing and heterogeneity of driver alterations accompanying the switch from benign adenoma to malignant carcinoma. In almost half of the cases, driver mutations specific to the carcinoma stage were not observed. In samples where carcinoma-specific alterations were present, TP53 mutations and chromosome 20 copy gains commonly accompanied the switch from adenomatous tissue to carcinoma. Remarkably, 40% and 50% of high-grade adenomas shared TP53 mutations and chromosome 20 gains, respectively, with their matched carcinomas. In addition, multi-regional analyses revealed greater heterogeneity of driver mutations in adenomas compared to their matched carcinomas. Conclusion: Genetic alterations in TP53 and chromosome 20 occur at the earliest histological stage in colorectal carcinomas (pTis and pT1). However, high-grade adenomas can share these alterations despite their histological distinction. Based on the well-defined sequence of CRC development, we suggest that the timing of genetic changes during neoplastic progression is frequently uncoupled from histological progression.
    • Mammalian cells expressing Escherichia coli O6-alkylguanine-DNA alkyltransferases are hypersensitive to dibromoalkanes.

      Abril, N; Margison, Geoffrey P; CRC Section of Genome Damage and Repair, Paterson Institute for Cancer Research, Christie Hospital (NHS) Trust, Manchester M20 4BX, U.K. (1999-06)
      The effect of expression of the DNA repair protein, O6-alkylguanine-DNA alkyltransferase, on the growth inhibitory effects of the dibromoalkanes (DBA) dibromomethane (DBM) and dibromoethane (DBE) was determined in Chinese hamster lung fibroblasts transfected with and expressing high levels of the Escherichia coli alkyltransferase (ATase) genes. These included the ogt gene and complete or truncated versions of the E. coli ada gene encoding either O6-alkylguanine (O6-alkG) or alkylphosphotriester (alkPT) ATase activities. The functional activity of the ATase in these cells was demonstrated by in vitro assay of cell extracts using 3H-methylated DNA as a substrate, and by the protection they provided against the growth inhibitory effects of methylating agents N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and N-methyl-N-nitrosourea (MNU) and the chloroethylating agent 1, 3-bis(2-chloroethyl)-1-nitrosourea (BCNU). However, cells expressing the full length or the O6-alkG ATase region, but not the alkPT ATase region, of Ada were found to be more sensitive to the growth inhibitory effects of the DBA; Ogt expression sensitized cells to DBM but not significantly to DBE. Addition of DBA to cell extracts depleted O6-alkG ATase activity on the methylated DNA substrate, but had no effect on alkPT ATase activity. This suggests that ATase-mediated sensitization of the intact cells may be related to the inactivation of the ATase protein. Addition to the cell culture medium of GSH or buthionine sulfoximine in attempts to augment or deplete cellular levels of GSH had no marked effect on the ATase-mediated sensitization to DBA. This suggests that rather than GSH-mediated DNA damage, the effect may be mediated by a DNA adduct caused by the oxidative metabolic pathway. These observations indicate that expression of ATase may have a detrimental effect on cellular sensitivity to environmentally relevant alkylating agents.
    • Mammary development, carcinomas and progesterone: role of Wnt signalling.

      Lamb, Rebecca; Harrison, Hannah; Clarke, Robert B; Breast Biology Group, Cancer Studies, University of Manchester, Paterson Institute for Cancer Research, Wilmslow Road, M20 4BX Manchester, UK. (2007)
      The mammary gland begins development during embryogenesis but after exposure to hormonal changes during puberty and pregnancy undergoes extensive further development. Hormonal changes are key regulators in the cycles of proliferation, differentiation, apoptosis and remodelling associated with pregnancy, lactation and involution following weaning. These developmental processes within the breast epithelium can be explained by the presence of a long-lived population of tissue-specific stem cells. The longevity of these stem cells makes them susceptible to accumulating genetic change and consequent transformation. The ovarian steroid progesterone, acting via the secreted factor Wnt4, is known to be essential for side branching of the mammary gland. One function of Wnt proteins is self-renewal of adult tissue stem cells, suggesting that progesterone may exert its effects within the breast, at least partly, by regulating the mammary stem cell population.
    • Mammary stem cells and breast cancer--role of Notch signalling

      Farnie, Gillian; Clarke, Robert B; Breast Biology Group, Division of Cancer Studies, Faculty of Medicine and Human Sciences, University of Manchester, Paterson Institute for Cancer Research, Wilmslow Road, Manchester, M20 4BX, UK. (2007-06)
      Adult stem cells are found in numerous tissues of the body and play a role in tissue development, replacement and repair. Evidence shows that breast stem cells are multipotent and can self renew, which are key characteristics of stem cells, and a single cell enriched with cell surface markers has the ability to grow a fully functional mammary gland in vivo. Many groups have extrapolated the cancer stem cell hypothesis from the haematopoietic system to solid cancers, where using in vitro culture techniques and in vivo transplant models have established evidence of cancer stem cells in colon, pancreas, prostate, brain and breast cancers. In the report we describe the evidence for breast cancer stem cells; studies consistently show that stem cell like and breast cancer initiating populations can be enriched using cell surface makers CD44+/CD24- and have upregulated genes which include Notch. Notch signalling has been highlighted as a pathway involved in the development of the breast and is frequently dysregulated in invasive breast cancer. We have investigated the role of Notch in a pre-invasive breast lesion, ductal carcinoma in situ (DCIS), and have found that aberrant activation of Notch signalling is an early event in breast cancer. High expression of Notch 1 intracellular domain (NICD) in DCIS also predicted a reduced time to recurrence 5 years after surgery. Using a non-adherent sphere culture technique we have grown DCIS mammospheres from primary DCIS tissue, where self-renewal capacity, measured by the number of mammosphere initiating cells, were increased from normal breast tissue. A gamma-secretase inhibitor, DAPT, which inhibits all four Notch receptors and a Notch 4 neutralising antibody were shown to reduce DCIS mammosphere formation, indicating that Notch signalling and other stem cell self-renewal pathways may represent novel therapeutic targets to prevent recurrence of pre-invasive and invasive breast cancer.
    • Mammographic density over time in women with and without breast cancer, in "Breast imaging: 13th International Workshop, IWDM 2016, Malmö, Sweden, June 19-22, 2016, proceedings."

      Humphrey, A; Harkness, E; Moschidis, E; Hurley, E; Foden, P; Bydder, M; Wilson, M; Gadde, S; Maxwell, A; Lim, Y; et al. (Springer, 2016)
    • Management of lateral skull base cancer: United Kingdom National Multidisciplinary Guidelines.

      Homer, Jarrod J; Lesser, T; Moffat, D; Slevin, N; Price, R; Blackburn, T; MAHSC, University of Manchester, Manchester (2016)
    • Management of organ transplant recipients attending a high-throughput skin cancer surgery and surveillance clinic in Queensland.

      Papier, K; Gordon, L G; Khosrotehrani, K; Isbel, N; Campbell, S; Griffin, A; Green, Adèle C; QIMR Berghofer Medical Research Institute, Population Health Department, Brisbane, Queensland, Australia (2018-07-13)
      The incidence of skin cancer in organ transplant recipients (OTRs) is very high due mainly to long-term immunosuppressive therapy. The problem is particularly severe for organ transplant recipients living in Queensland, Australia, resulting in significant mortality.
    • Management of the menopause in cancer survivors.

      Clemons, Mark; Clamp, Andrew R; Anderson, Beverley; Division of Medical Oncology, Toronto-Sunnybrook Regional Cancer Centre, Ont., Canada. mark.clemons@tsrcc.on.ca (2002-12)
      The consequences of premature menopause are of great importance to cancer survivors. Oestrogen replacement therapy (with and without added progestins) is the most extensively researched agent for the treatment and prevention of menopausal problems. While this may be appropriate for symptom control in patients with tumours that are not hormone responsive, patients with hormone dependent tumours will require safe and effective alternative treatments for menopausal symptoms. This paper will discuss both the short-term and long-term consequences of the menopause in cancer survivors and will also offer various management strategies.
    • Manchester Intermittent versus Daily Diet App Study (MIDDAS): A pilot randomized controlled trial in patients with type 2 diabetes

      McDiarmid, S.; Harvie, Michelle N; Johnson, R.; Vyas, A.; Aglan, A.; Moran, J.; Ruane, H.; Hulme, A.; Sellers, K.; Issa, B. G.; et al. (2021)
      Aims: To test the feasibility and potential efficacy of remotely supported intermittent low energy diets (ILEDs) and continuous low energy diets (CLEDs) in people with type 2 diabetes (T2D) and the feasibility of a Randomized Controlled Trial (RCT) comparing the two approaches. Materials and methods: Seventy-nine adults with overweight/obesity and T2D (≤8 years duration) were randomized 1:1 to CLED (eight weeks/56 days of daily Optifast 820kcal (3430kJ) diet) or isoenergetic ILED (two days of Optifast and five days of a Mediterranean diet/week for 28 weeks). Weight maintenance/continued weight loss was undertaken for the remainder of the 52 weeks. Both groups received frequent telephone and/or the Oviva app support. Feasibility outcomes included study uptake, retention, app usage, dietary adherence, weight loss, and change in HbA1c at 52 weeks. Results: We enrolled 39 ILED and 40 CLED participants and 27 (69%) ILED and 30 CLED (75%) attended 52-week follow-up. Eighty-nine percent (70/79) started using the app and 86% (44/51) still used the app at 52 weeks. Intention-to-treat analysis at 52 weeks showed percentage weight loss was mean (CI) -5.4% (-7.6, -3.1%) for ILED and -6.0% (-7.9, -4.0%) for CLED. HbA1c<48mmol/mol was achieved in 42% of both groups. Mean (CI) changes in the T2D medication effect score (MES) were 0.0008 (-0.3, 0.3) for ILED and -0.5 (-0.8, -0.3) for CLED. Conclusion: The study demonstrates the feasibility and potential efficacy of remotely delivered ILED and CLED programs for weight loss and HbA1c reduction, and the feasibility of an RCT comparing the two approaches.
    • Map3k1 loss cooperates with Braf(V600E) to drive melanomagenesis

      Trucco, Lucas D; Mundra, Piyushkumar A; Garcia-Martinez, Pablo; Hogan, Kate; Baenke, Franziska; Dhomen, Nathalie; Pavet, Valeria R; Marais, Richard; Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, (2020)
      No abstract available
    • MAPK pathway activation in the embryonic pituitary results in stem cell compartment expansion, differentiation defects and provides insights into the pathogenesis of papillary craniopharyngioma.

      Haston, S; Pozzi, S; Carreno, G; Manshaei, S; Panousopoulos, L; Gonzalez-Meljem, J; Apps, J R; Virasami, A; Thavaraj, S; Gutteridge, A; et al. (2017-05-15)
      Despite the importance of the RAS-RAF-MAPK pathway in normal physiology and disease of numerous organs, its role during pituitary development and tumourigenesis remains largely unknown. Here we show that the over-activation of the MAPK pathway, through conditional expression of the gain-of-function alleles BrafV600E and KrasG12D in the developing mouse pituitary, results in severe hyperplasia and abnormal morphogenesis of the gland by the end of gestation. Cell-lineage commitment and terminal differentiation are disrupted, leading to a significant reduction in numbers of most of the hormone-producing cells before birth, with the exception of corticotrophs. Of note, Sox2+ve stem cells and clonogenic potential are drastically increased in the mutant pituitaries. Finally, we reveal that papillary craniopharyngioma (PCP), a benign human pituitary tumour harbouring BRAF p.V600E also contains Sox2+ve cells with sustained proliferative capacity and disrupted pituitary differentiation. Together, our data demonstrate a critical function of the MAPK pathway in controlling the balance between proliferation and differentiation of Sox2+ve cells and suggest that persistent proliferative capacity of Sox2+ve cells may underlie the pathogenesis of PCP.
    • Mapping dynamic epithelial cell proliferative activity within the oral cavity of man: a new insight into carcinogenesis?

      Thomson, P J; Potten, Christopher S; Appleton, D R; Department of Oral & Maxillofacial Surgery, The Dental School, University of Newcastle upon Tyne, UK. (1999-10)
      Our aim was to characterize epithelial cell proliferative activity within the oral cavity and to find out if there were differences between sites with high and low incidence of cancer. A total of 105 samples of clinically normal mucosa were harvested from various intra-oral sites. Excised specimens were incubated in vitro with tritiated thymidine and bromodeoxyuridine to 'double label' cells undergoing DNA synthesis, and enable calculation of the duration of S phase and estimation of variables of cell flux to and from S. Mean labelling indices (percentage of cells within the S phase of the cell cycle) were highest in the floor of mouth (12.3%) and ventral tongue (10.1%), while activity was lowest in the dorsum of tongue (4.3%) and the palate (7.2%), P<0.001. In general, both cell influx and the duration of S increased proportionally to the labelling index. Sites with a high incidence of cancer were characterized by high labelling indices, increased cell influx and a prolonged S phase.
    • Mapping of 22 new ESTs around a tumor suppressor gene and a senescence gene at 6q16-->q21.

      Morelli, C; Cardona, F; Boyle, John M; Negrini, M; Barbanti-Brodano, G; Department of Experimental and Diagnostic Medicine, University of Ferrara, Italy. (1997)
      Twenty two expressed sequence tags (ESTs) have been mapped at the border of 6q16-->q21 and at the proximal end of 6q21, a candidate for two tumor suppressor genes and a senescence gene. Use of a translocation and deletion hybrid panel together with a 4-Mb YAC contig allowed us to precisely define the position of the ESTs. Thirteen ESTs were placed within the 4-Mb interval at the proximal portion of 6q21 using a restriction map of the YAC contig, seven ESTs span a 2-Mb region on the 6q16-->q21 border, and two are distal to the contig. Refinement of the localization of these ESTs will provide substantial assistance in identifying new genes within the region 6q16-->q21.
    • Mapping of gene loci in the Q13-Q15 region of chromosome 12.

      Mitchell, Erika L D; White, Gavin R M; Santibanez-Koref, Mauro F; Varley, Jennifer; Heighway, Jim; Cancer Research Campaign Department of Cancer Genetics, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester. (1995-06)
      The gene loci CDK4, GLI, CHOP and MDM2 have been mapped to the q13-q15 region of chromosome 12. Using fluorescence in situ hybridization onto simultaneously DAPI-banded metaphase chromosomes and interphase nuclei, we have more precisely mapped and ordered these loci, together with a number of Genethon microsatellite markers. GLI and CHOP localize to 12q13.3-14.1, CDK4 to 12q14 and MDM2 to 12q14.3-q15, and the gene order is cen-GLI/CHOP-CDK4-MDM2. The Genethon microsatellites D12S80 and D12S83 flank MDM2.
    • Mapping of OGT in the E.coli chromosome.

      Potter, P M; Harris, L; Margison, Geoffrey P; Department of Carcinogenesis, Paterson Institute for Cancer Research, Christie Hospital and Holt Radium Institute, Manchester, UK. (1989-12-25)