• Actinic keratosis-related signs predictive of squamous cell carcinoma in renal transplant recipients: a nested case-control study.

      Jiyad, Z; O'Rourke, P; Soyer, H; Green, Adèle C; Cancer and Population Studies Group, QIMR Berghofer Medical Research Institute, Locked Bag 2000, Royal Brisbane Hospital, Brisbane, QLD 4029, Australia. (2017-04)
      Squamous cell carcinoma (SCC) and intraepidermal carcinoma (IEC) commonly arise in actinically damaged skin.
    • The action of rat cytosol enzymes on some methylated nucleic acid components produced by the carcinogenic N-nitroso compounds.

      O'Connor, Peter J; Saffhill, Roy; Paterson Laboratories, Christie Hospital and Holt Radium Institute, Manchester (1979-06)
      The stabilities of several alkylated nucleic acid components have been examined in the presence of cytosol extracts from a variety of rat tissues. An activity capable of demethylating O6-methyldeoxyguanosine was readily detectable in all tissues examined; arranged in approximate order of decreasing specific activity these are as follows: small intestine, spleen, kidney, lung, liver, skin, heart and brain. The in vitro requirements for the activity derived from liver and the observations that O6-methylguanine and its deoxynucleoside 5'-monophosphate are insensitive to the action of these extracts suggests that this activity may be due to an enzyme which resembles adenosine deaminase. In contrast to the ready degradation of O6-methyldeoxyguanosine the corresponding ethyl derivative was degraded very much more slowly but there was no evidence for other activities against the O4- and O2-methyldeoxythymidines. Similarly, no demethylation of the N-substituted deoxynucleosides, 3-methyldeoxycytidine 3-methldeoxythymidine, 1-methyldeoxyadenosine and 7-methyldeoxyguanosine, was detected.
    • The action spectrum for induction of chronic actinic dermatitis is similar to that for sunburn inflammation.

      Menagé, H D; Harrison, G I; Potten, Christopher S; Young, A R; Hawk, J L; Department of Photobiology, St. John's Institute of Dermatology, United Medical School of Guy's Hospital, London. (1995-12)
      The action spectrum for induction of the abnormal cutaneous response at 24 h in the photosensitivity disorder chronic actinic dermatitis (CAD) was determined in 15 patients and found to be the same in shape as that for normal sunburn in fair-skinned individuals at 24 h, as determined for 47 control volunteers, although displaced in magnitude. This suggests that an endogenous chromophore(s), the same as or similar to that/those responsible for human sunburn, may be responsible for initiation of the abnormal reaction to irradiation in CAD, and that the putative antigen associated with the CAD reaction may be derived from that/those or associated molecules.
    • Actions of the haemopoietic stem cell proliferation inhibitor.

      Lord, Brian I; Wright, Eric G; Lajtha, L G; Paterson Laboratories, Christie Hospital and Holt Radium Institute, Manchester (1979-06-15)
    • Activated c-SRC in ductal carcinoma in situ correlates with high tumour grade, high proliferation and HER2 positivity.

      Wilson, G R; Cramer, Angela; Welman, Arkadiusz; Knox, W Fiona; Swindell, Ric; Kawakatsu, H; Clarke, Robert B; Dive, Caroline; Bundred, Nigel J; Department of Academic Surgery, Research and Education Building 2nd Floor, South Manchester University Hospital, Wythenshawe, Manchester, UK. (2006-11-20)
      Overexpression and/or activity of c-Src non-receptor tyrosine kinase is associated with progression of several human epithelial cancers including breast cancer. c-Src activity in 'pure' ductal carcinoma in situ (DCIS) was measured to assess whether this predicts recurrence and/or correlates with HER2 expression and other clinical parameters. Activated c-Src levels were evaluated in DCIS biopsies from 129 women, with median follow-up at 60 months. High levels of activated c-Src correlated with HER2 positivity, high tumour grade, comedo necrosis and elevated epithelial proliferation. In univariate analysis, high activated c-Src level associated with lower recurrence-free survival at 5 years (P=0.011). Thus, high c-Src activity may identify a subset of DCIS with high risk of recurrence or progression to invasive cancer where therapeutics targeting c-Src may benefit this patient subset.
    • An activated protein kinase C alpha gives a differentiation signal for hematopoietic progenitor cells and mimicks macrophage colony-stimulating factor-stimulated signaling events.

      Pierce, A; Heyworth, Clare M; Nicholls, S E; Spooncer, Elaine; Dexter, T Michael; Lord, J M; Owen-Lynch, P J; Wark, G; Whetton, Anthony D; Leukaemia Research Fund Cellular Development Unit, University of Manchester Institute of Science and Technology, Manchester, M60 1QD, United Kingdom. (1998-03-23)
      Highly enriched, bipotent, hematopoietic granulocyte macrophage colony-forming cells (GM-CFC) require cytokines for their survival, proliferation, and development. GM-CFC will form neutrophils in the presence of the cytokines stem cell factor and granulocyte colony-stimulating factor, whereas macrophage colony-stimulating factor leads to macrophage formation. Previously, we have shown that the commitment to the macrophage lineage is associated with lipid hydrolysis and translocation of protein kinase C alpha (PKCalpha) to the nucleus. Here we have transfected freshly prepared GM-CFC with a constitutively activated form of PKCalpha, namely PKAC, in which the regulatory domain has been truncated. Greater than 95% of the transfected cells showed over a twofold increase in PKCalpha expression with the protein being located primarily within the nucleus. The expression of PKAC caused macrophage development even in the presence of stimuli that normally promote only neutrophilic development. Thus, M-CSF-stimulated translocation of PKCalpha to the nucleus is a signal associated with macrophage development in primary mammalian hematopoietic progenitor cells, and this signal can be mimicked by ectopic PKAC, which is also expressed in the nucleus.
    • Activating transcription factor ATF2 negatively regulates the expression of endothelial notch ligands

      Olivares, Ivonne; Kalyanakrishnan, Krithika; Ahmed, Suhail; Murcott, Clare; Wilkinson, Robert N; Cotton, James; Breitwieser, Wolfgang; Morris, Mark R; Armesilla, Angel L; RIHS, FSE, University of Wolverhampton (2019)
    • Activation of cyclin D1-kinase in murine fibroblasts lacking both p21(Cip1) and p27(Kip1).

      Sugimoto, Masataka; Martin, Nicholas; Wilks, Deepti P; Tamai, Katsuyuki; Huot, Thomas J G; Pantoja, Cristina; Okumura, Ko; Serrano, Manuel; Hara, Eiji; Cancer Research UK, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester M20 4BX, UK. (2002-11-21)
      Deregulation of D-type cyclin-dependent kinases (CDK4 and 6) is widely observed in various human cancers, illustrating their importance in cell cycle control. Like other cyclin-dependent kinases (CDKs), assembly with cyclins is the most critical step for activation of CDK4/6. As previously reported elsewhere, we observed that the level of cyclinD1-CDK4 complex and its associated kinase activity were significantly low in asynchronously proliferating mouse embryo fibroblasts lacking both p21(Cip1) and p27(Kip1) (p21/p27-null MEFs). These evidences imply that p21(Cip1) and p27(Kip1) CDK inhibitors are 'essential activators' of cyclin D-kinases. We, however, discovered here that both the assembly and activation of cyclin D1-CDK4 complex occur when quiescent p21/p27-null MEFs were stimulated to re-enter the cell cycle. This mitogen-induced cyclin D1-kinase activity was blocked by overexpression of p16(INK4a) and resulted in the inhibition of S phase entry in p21/p27-null MEFs. Furthermore, ectopic expression of p34(SEI-1), a mitogen-induced CDK4 binding protein, increased the levels of active cyclinD1-CDK4 complex in asynchronously proliferating p21/p27-null MEFs. Together, our results suggest that there are several independent ways to stimulate the assembly of cyclin D1-CDK4 kinases. Although p21(Cip1) and p27(Kip1) play a role in this process, our results demonstrate that additional mechanisms must occur in G0 to S phase transition.
    • Activation of granulocyte-macrophage colony-stimulating factor and interleukin-3 receptor subunits in a multipotential hematopoietic progenitor cell line leads to differential effects on development.

      Evans, Caroline A; Pierce, Andrew; Winter, Sandra A; Spooncer, Elaine; Heyworth, Clare M; Whetton, Anthony D; Department of Biomolecular Sciences, Leukaemia Research Fund Cellular Development Unit, Manchester, United Kingdom. (1999-09-01)
      Activation of specific cytokine receptors promotes survival and proliferation of hematopoietic progenitor cells but their role in the control of differentiation is unclear. To address this issue, the effects of human interleukin-3 (hIL-3) and human granulocyte-macrophage colony-stimulating factor (hGM-CSF) on hematopoietic development were investigated in hematopoietic progenitor cells. Murine multipotent factor-dependent cell-Paterson (FDCP)-mix cells, which can self-renew or differentiate, were transfected with the genes encoding the unique alpha and/or shared beta(c) human hIL-3 receptor (hIL-3 R) or hGM-CSF receptor (hGM R) subunits by retroviral gene transfer. Selective activation of hIL-3 Ralpha,beta(c) or hGM Ralpha,beta(c) transfects by hIL-3 and hGM-CSF promoted self-renewal and myeloid differentiation, respectively, over a range of cytokine (0.1 to 100 ng/mL) concentrations. These qualitatively distinct developmental outcomes were associated with different patterns of protein tyrosine phosphorylation and, thus, differential signaling pathway activation. The cell lines generated provide a model to investigate molecular events underlying self-renewal and differentiation and indicate that the alpha subunits act in combination with the hbeta(c) to govern developmental decisions. The role of the alpha subunit in conferring specificity was studied by using a chimeric receptor composed of the extracellular hIL-3 Ralpha and intracellular hGM Ralpha subunit domains. This receptor promoted differentiation in response to hIL-3. Thus, the alpha subunit cytosolic domain is an essential component in determining cell fate via specific signaling events.
    • Activation of the redox sensor Pap1 by hydrogen peroxide requires modulation of the intracellular oxidant concentration.

      Vivancos, Ana P; Castillo, Esther A; Jones, Nic; Ayte, Jose; Hidalgo, Elena; Cell Signalling Unit, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, C/Dr Aiguader 80, E-08003 Barcelona, Spain. (2004-06)
      The transcription factor Pap1 and the MAP kinase Sty1 are key regulators of hydrogen peroxide-induced responses in Schizosaccharomyces pombe. Pap1 can be activated quickly at low, but not high, hydrogen peroxide concentrations. The MAP kinase Sty1 has been reported to participate in Pap1 activation by the oxidant. Here, we provide biochemical and genetic evidence for the in vivo formation of a hydrogen peroxide-induced disulphide bond in Pap1, which precedes the rapid and reversible nuclear accumulation of the transcription factor. We show that activation of the Sty1 cascade before the oxidative insult, or overexpression of the Sty1-regulated genes ctt1 (encoding catalase) or gpx1 (encoding glutathione peroxidase), can accelerate Pap1 entry even at high doses of hydrogen peroxide. In fact, the lack of Sty1 impedes Pap1 nuclear localization, but only at high doses of the oxidant. We propose that, whereas low doses of hydrogen peroxide lead directly to Pap1 oxidation-activation, high concentrations of the oxidant initially activate the Sty1 pathway, with the consequent increase in scavenging enzymes, which in turn helps to decompose the excess of hydrogen peroxide and achieve an appropriate concentration for the subsequent activation of Pap1. Our results also suggest that activation of Sty1 at high doses of hydrogen peroxide may also be required to trigger other antioxidant activities such as those reverting the overoxidation of cysteine residues at the Pap1 pathway.
    • Active nuclear pore complexes in Chironomus: visualization of transporter configurations related to mRNP export.

      Kiseleva, Elena; Goldberg, Martin W; Allen, Terence D; Akey, C W; CRC Department of Structural Cell Biology, Paterson Institute for Cancer Research, Cristie Hospital National Health Service Trust, Manchester, M20 9BX, UK. (1998-01)
      The Nuclear Pore Complex (NPC) regulates nucleocytoplasmic transport by providing small channels for passive diffusion and multiple docking surfaces that lead to a central translocation channel for active transport. In this study we have investigated by high resolution scanning and transmission electron microscopy the dynamics of NPC structure in salivary gland nuclei from Chironomus during Balbiani ring (BR) mRNP translocation, and present evidence of rearrangement of the transporter related to mRNP export. Analysis of the individual NPC components verified a strong evolutionary conservation of NPC structure between vertebrates and invertebrates. The transporter is an integral part of the NPC and is composed of a central short double cylinder that is retained within the inner spoke ring, and two peripheral globular assemblies which are tethered to the cytoplasmic and nucleoplasmic coaxial rings by eight conserved internal ring filaments. Distinct stages of BR mRNP nuclear export through the individual NPC components were directly visualized and placed in a linear transport sequence. The BR mRNP first binds to the NPC basket, which forms an expanded distal basket ring. In this communication we present stages of BR mRNP transport through the nucleoplasmic, central and cytoplasmic transporter subunits, which change their conformation during mRNP translocation, and the emergence of mRNP into the cytoplasm. We propose that the reorganization of the basket may be driven, in part, by an active translocation process at the transporter. Furthermore, the images provide dramatic evidence that the transporter functions as a central translocation channel with transiently open discrete gates in its globular assemblies. A model of NPC transporter reorganization accompanied with mRNP translocation is discussed.
    • Activity of fotemustine in medulloblastoma and malignant glioma xenografts in relation to O6-alkylguanine-DNA alkyltransferase and alkylpurine-DNA N-glycosylase activity.

      Vassal, G; Boland, I; Terrier-Lacombe, M J; Watson, Amanda J; Margison, Geoffrey P; Vénuat, A M; Morizet, J; Parker, F; Lacroix, C; Lellouch-Tubiana, A; et al. (1998-02)
      Fotemustine is a chloroethylnitrosourea with antitumor activity in disseminated melanoma and adult primary brain tumors. Because new drugs are required for the treatment of medulloblastoma in children, we evaluated the preclinical antitumor activity of fotemustine in four s.c. medulloblastoma xenografts, in comparison with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). Both drugs were administered as a single i.p. injection to nude mice bearing advanced-stage tumor. Fotemustine displayed significant antitumor activity in three of four medulloblastoma xenografts; two, IGRM34 and IGRM57, were highly sensitive, with 37 and 100% tumor-free survivors, respectively, more than 120 days after treatment at the highest nontoxic dose (50 mg/kg). Fotemustine was also highly active in a malignant glioma xenograft (IGRG88; five of six tumor-free survivors on day 177). Fotemustine proved to be significantly more active than BCNU in IGRM34 and the glioma xenograft IGRG88. The DNA repair protein O6-alkylguanine-DNA alkyltransferase (ATase) was detected in all tumor xenografts, ranging in activity from 6 to 892 fmol/mg protein. The high in vivo sensitivity to fotemustine and BCNU observed in three xenografts was clearly associated with a low ATase activity (> 20 fmol/mg), whereas the two poorly sensitive or refractory medulloblastoma xenografts showed high ATase activity (> 500 fmol/mg). Alkylpurine-DNA N-glycosylase activity was detected in all tumor xenografts but at levels ranging only from 513 to 1105 fmol/mg/h; no consistent relationship was found between alkylpurine-DNA N-glycosylase activity and the in vivo sensitivity to the two chloroethylnitrosoureas. The improved activity and tolerance of fotemustine in comparison with BCNU in pediatric medulloblastoma xenografts strongly support the clinical development of this agent in children with brain tumors, in which ATase should be examined as a potential prognostic indicator.
    • Activity profile of the novel aziridinylbenzoquinones MeDZQ and RH1 in human tumour xenografts.

      Cummings, Jeffrey; Ritchie, Alison; Butler, John; Ward, Timothy H; Langdon, Simon; Cancer Research UK, Edinburgh Medical Oncology Unit, Western General Hospital, Edinburgh, EH4 2XR, U.K. jcummings@picr.man.ac.uk (2009-09-23)
      BACKGROUND: RH1 and MeDZQ represent novel aziridinylbenzoquinones that can be activated by DT-diaphorase to form unique DNA lesions. RH1 is due to enter a phase 1 clinical trial in the United Kingdom in the summer of 2003, where pharmacodynamic monitoring of DT-diaphorase will be performed. MATERIALS AND METHODS: The antitumour efficacy of RH1 and MeDZQ has been studied in 4 human xenografts (3 non-small cell lung cancer and 1 colon cancer), and compared to the level of constitutive DT-Diaphorase activity measured by the DCPIP assay. RESULTS: The 4 xenografts exhibited a wide range of DT-diaphorase activity (4.8-303 nmol/min/mg). Greater antitumour activity was recorded in the xenografts expressing high levels of DT-diaphorase (e.g. NX002, DT-diaphorase activity, 303 +/- 52 nmol/min/mg, T/C to MeDZQ, 33.3% and to RH1, 43.4%). CONCLUSION: These data add in vivo support to a role for DT-Diaphorase in the antitumour activity of RH1.
    • Acute lymphoblastic leukaemia cells produce large extracellular vesicles containing organelles and an active cytoskeleton.

      Johnson, Suzanne M; Dempsey, Clare E; Parker, Catriona; Mironov, Aleksandr; Bradley, Helen; Saha, Vaskar; Children's Cancer Group, Division of Molecular and Clinical Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester , Manchester (2017)
      Extracellular vesicles have been described in non-paracrine cellular interactions in cancer. We report a similar phenomenon in B-cell precursor (BCP) acute lymphoblastic leukaemia (ALL). Using advanced microscopy and high throughput screening, we further characterise a subset of large vesicles (LEVs) identified in cell lines, murine models of human BCP-ALL and clinical samples. Primary ALL blasts and cell lines released heterogeneous anucleate vesicles <6 micron into extracellular fluids. Larger LEVs were enclosed in continuous membranes, contained intact organelles and demonstrated an organised cytoskeleton. An excess of circulating CD19-positive LEVs were observed in diagnostic samples and isolated from mice engrafted with BCP-ALL primary cells. LEVs exhibited dynamic shape change in vitro and were internalised by other leukaemic cell lines leading to phenotypic transformation analogous to the cell of origin. In patient-derived xenografts, LEVs were released by primary ALL cells into extracellular spaces and internalised by murine mesenchymal cells in vivo. Collectively these data highlight the heterogeneity but accessibility of LEVs in clinical samples and their potential to provide a unique insight into the biology of the cell of origin and to their development as novel biomarkers to aid diagnosis and improve therapeutic outcomes.
    • Acute response of mouse kidney clonogens to fractionated irradiation in situ and then assayed in primary culture.

      Jen, Yee-Min; Hendry, Jolyon H; Cancer Research Campaign Department of Radiobiology, Paterson Institute for Cancer Research, Christie Hospital and Holt Radium Institute, Manchester, UK. (1991-02)
      Although the difference in sensitivity to the changes in dose fraction size between early-responding and late-responding tissues is well established, the underlying mechanisms in terms of target-cell responses are not yet clearly identified for any tissue. The radiosensitivity of mouse kidney cells after in situ single-dose, 2, 8, and 16 fraction X-irradiations was measured in primary culture using a clonogenic assay. The assay was made 12 h after single doses or 12 h after the last dose of the multifraction regimens. When analysed using the linear-quadratic model, as predicted the individual alpha components for all the different fractionation schedules were not significantly different, and the changes in the beta values were consistent with those expected on the basis of the reciprocal fraction numbers. When all four data sets were integrated to derive a common alpha/beta ratio, the result was 4.4 +/- 1.3 (1SE) Gy, or 2.8 +/- 0.9 Gy (a better fit) if the single-dose data set was excluded. These values fall into the range reported for kidney using assays of tissue function at long times after irradiation. Hence, it has been shown for the first time that the fractionation sensitivity of a late-responding organ is mimicked by that of a clonogenic cell population in that organ. The evidence also suggests that the time available prior to fixation of potentially lethal damage does not influence the low alpha/beta ratio observed for the kidney.
    • ADAPT: a database of affymetrix probesets and transcripts.

      Leong, Hui Sun; Yates, Tim; Wilson, Claire L; Miller, Crispin J; Paterson Institute for Cancer Research, Wilmslow Road, Manchester M20 4BX, UK. (2005-05-15)
      ADAPT is an online database providing comprehensive mappings between Affymetrix probes and RefSeq and Ensembl transcripts. ADAPT was designed to help interpret microarray experiments by providing a means to explore the many-to-many relationships that exist between probes, probesets, transcripts and genes. AVAILABILITY: ADAPT can be queried via the web at http://bioinformatics.picr.man.ac.uk/adapt
    • Adaptive correction of scatter and random events for 3-D backprojected PET data

      Reader, Andrew J; Zhao, Sha; Julyan, Peter J; Hastings, David L; Zweit, Jamal; Department of Instrumentation and Analytical Science, UMIST, Manchester, M60 1QD (2001)
    • Adding more content to screening: reactivation of FOXO as a therapeutic strategy.

      Zanella, Fabian; Carnero, Amancio; Experimental Therapeutics Programme, Spanish National Cancer Research Centre, Madrid, Spain. (2009-10)
      The discovery of novel targets that can be pharmacologically exploited to lead to a better disease outcome has long been an aim of biomedical research. At present, the technology and robotisation available have pushed the search for novel molecules to a high-throughput screening (HTS) context, making it possible to screen several hundreds of compounds or genes in a single day. High-content screenings (HCS) have added a refined complexity to the screening processes, as the information drawn from an image- based assay is more complete than the monoparametric readouts obtained in classical HTS assays. Here, we review the development of HCS platforms to identify molecules influencing FOXO nuclear relocation and activation as pharmacological targets, their applicability and the future directions of the screening field.
    • Addition of neutron and gamma-ray fractions for intestinal damage.

      Hendry, Jolyon H; Rosenberg, I; Greene, D (1976-11)
      The microcolony assay technique has been used to test the validty of summing equivalent doses per fraction of 14 MeV neutrons and gamma rays for mouse intestinal damage. For a 4-daily fraction schedule, in which the first one or two fractions are given as neutrons and the remainder as gamma rays, combined dose fractions calculated from a 4-fraction schedule of either radiation type alone produce the same level of damage within the limits of accuracy of the experiment.
    • Additive interaction between tamoxifen and rifampicin in human biliary tract carcinoma cells.

      West, Catharine M L; Reeves, S J; Brough, W; Department of Radiobiology, Paterson Institute for Cancer Research, Manchester, U.K. (1990-12-03)
      A novel two-drug combination of tamoxifen and rifampicin has been investigated for the treatment of biliary tract-associated malignancies. Their effects, alone and in combination, on human tumour cells were studied using two pancreatic carcinoma cell lines. MIA PaCa-2 and AsPC-1, and a gall bladder carcinoma cell line, G-415. Inhibition of growth was used as an endpoint. The cells differed in sensitivity to equimolar doses of the two drugs given as single agents. Combined doses of rifampicin and tamoxifen resulted in growth inhibition to an extent that was suggestive of additive or synergistic drug effects. More detailed analysis was carried out, involving the production of an 'envelope of additivity' for each cell line. An additive effect of drug combination was shown to occur in all three cell lines, thus providing a basis for use of this novel two-drug combination in the treatment of biliary tract-associated malignancies.