• 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)
    • Mapping of RXRB to human chromosome 6p21.3.

      Fitzgibbon, J; Gillett, G T; Woodward, K J; Boyle, John M; Wolfe, J; Povey, S; Department of Genetics and Biometry, Galton Laboratory, University College London. (1993-07)
      Retinoid X Receptor beta (RXRB) is a member of the retinoid X receptor (RXR) family of nuclear receptors which are involved in mediating the effects of retinoic acid (RA). We have confirmed the localization of RXRB to chromosome 6 and we have mapped the gene to chromosome 6p21.3-p21.1 by PCR amplification of 5' untranslated sequence in panels of rodent-human somatic cell hybrids and to 6p21.3 by fluorescent in situ hybridization.
    • Mapping of the G1 phase of a mammalian cell cycle.

      Naha, P M; Meyer, A L; Hewitt, Kathleen; Paterson Laboratories, Christie Hospital and Holt Radium Institute, Manchester (1975-11-06)
    • Mapping regions of allelic imbalance on chromosome-1 in human breast-cancer.

      Hoggard, Nigel; Brintnell, Bill; Hey, Yvonne; Jones, David; Michell, Erika L D; Varley, Jennifer (1994)
    • Marimastat as maintenance therapy for patients with advanced gastric cancer: a randomised trial.

      Bramhall, S R; Hallissey, M T; Whiting, J; Scholefield, J; Tierney, G; Stuart, R C; Hawkins, Robert E; McCulloch, P; Maughan, T; Brown, P D; et al. (2002-06-17)
      This randomised, double-blind, placebo-controlled study was designed to evaluate the ability of the orally administered matrix metalloproteinase inhibitor, marimastat, to prolong survival in patients with non-resectable gastric and gastro-oesophageal adenocarcinoma. Three hundred and sixty-nine patients with histological proof of adenocarcinoma, who had received no more than a single regimen of 5-fluorouracil-based chemotherapy, were randomised to receive either marimastat (10 mg b.d.) or placebo. Patients were treated for as long as was tolerable. The primary endpoint was overall survival with secondary endpoints of time to disease progression and quality of life. At the point of protocol-defined study completion (85% mortality in the placebo arm) there was a modest difference in survival in the intention-to-treat population in favour of marimastat (P=0.07 log-rank test, hazard ratio=1.23 (95% confidence interval 0.98-1.55)). This survival benefit was maintained over a further 2 years of follow-up (P=0.024, hazard ratio=1.27 (1.03-1.57)). The median survival was 138 days for placebo and 160 days for marimastat, with 2-year survival of 3% and 9% respectively. A significant survival benefit was identified at study completion in the pre-defined sub-group of 123 patients who had received prior chemotherapy (P=0.045, hazard ratio=1.53 (1.00-2.34)). This benefit increased with 2 years additional follow-up (P=0.006, hazard ratio=1.68 (1.16-2.44)), with 2-year survival of 5% and 18% respectively. Progression-free survival was also significantly longer for patients receiving marimastat compared to placebo (P=0.009, hazard ratio=1.32 (1.07-1.63)). Marimastat treatment was associated with the development of musculoskeletal pain and inflammation. Events of anaemia, abdominal pain, jaundice and weight loss were more common in the placebo arm. This is one of the first demonstrations of a therapeutic benefit for a matrix metalloproteinase inhibitor in cancer patients. The greatest benefit was observed in patients who had previously received chemotherapy. A further randomised study of marimastat in these patients is warranted.
    • Markedly elevated levels of an endogenous sarc protein in a hemopoietic precursor cell line.

      Scolnick, E; Weeks, M; Shih, T; Ruscetti, S; Dexter, T Michael; Laboratory of Tumor Virus Genetics, National Cancer Institute, Bethesda, Maryland 20205. (1981-01)
      The src gene product of Harvey murine sarcoma virus is a 21,000-dalton guanine nucleotide-binding protein. We have recently shown that a wide variety of vertebrate cell strains and cell lines express much lower levels of an endogenous p21 immunologically related to the Harvey murine sarcoma virus-coded p21. In this report, we have examined the levels of endogenous p21 in a unique hemopoietic precursor cell line, 416B, which was originally described as a continuous cell line of a hemopoietic stem cell, CFU-S. The currently available 416B cells express markedly elevated levels of endogenous p21. The level of endogenous p21 in the 416B cells is 5- to 10-fold higher than the level of p21 in Harvey murine sarcoma virus-infected cells and more than 100 times higher than the level of endogenous p21 that we have observed in a variety of other fresh or cultured cells. The results indicate that marked regulation of the levels of an endogenous sarc gene product can occur, and speculation about a possible role for endogenous p21 in normal hemopoietic stem cells is discussed.
    • Markedly elevated levels of an endogenous sarc protein in a hemopoietic precursor cell line.

      Scolnick, E; Weeks, M; Shih, T; Ruscetti, S; Dexter, T Michael; Laboratory of Tumor Virus Genetics, National Cancer Institute, Bethesda, Maryland 20205. (1981-01)
      The src gene product of Harvey murine sarcoma virus is a 21,000-dalton guanine nucleotide-binding protein. We have recently shown that a wide variety of vertebrate cell strains and cell lines express much lower levels of an endogenous p21 immunologically related to the Harvey murine sarcoma virus-coded p21. In this report, we have examined the levels of endogenous p21 in a unique hemopoietic precursor cell line, 416B, which was originally described as a continuous cell line of a hemopoietic stem cell, CFU-S. The currently available 416B cells express markedly elevated levels of endogenous p21. The level of endogenous p21 in the 416B cells is 5- to 10-fold higher than the level of p21 in Harvey murine sarcoma virus-infected cells and more than 100 times higher than the level of endogenous p21 that we have observed in a variety of other fresh or cultured cells. The results indicate that marked regulation of the levels of an endogenous sarc gene product can occur, and speculation about a possible role for endogenous p21 in normal hemopoietic stem cells is discussed.
    • A 'marker switch' approach for targeted mutagenesis of genes in Schizosaccharomyces pombe.

      MacIver, Fiona H; Glover, David M; Hagan, Iain M; Paterson Institute for Cancer Research, Wilmslow Road, Manchester M20 4BX, UK. (2003-05)
      The completion of the Schizosaccharomyces pombe genome sequencing project has led to a dramatic acceleration of gene characterization in this system. Once a gene has been identified, the challenge then comes in using reverse genetics to generate a range of mutants in this gene of interest so that the powerful genetics and wealth of genetic backgrounds available in Sz. pombe can be exploited to study the function of the newly identified molecule. Beyond simple PCR-tagging approaches, the high frequency with which illegitimate recombination occurs in Sz. pombe has made the manipulation of some loci complex, time consuming and a process of trial and error. Here we describe a simple 'marker switch' approach that enables the rapid selection of integration events at the locus of interest from an excessive background of integration at heterologous sites. We use the generation of temperature-sensitive mutations in the plo1(+) gene to validate this approach.