• Bioinformatics goes back to the future.

      Miller, Crispin J; Attwood, Teresa K; Paterson Institute for Cancer Research, Christie Hospital, Wilmslow Road, Withington, Manchester M20 4BX, UK. cmiller@picr.man.ac.uk (2003-02)
      The need to turn raw data into knowledge has led the bioinformatics field to focus increasingly on the manipulation of information. By drawing parallels with both cryptography and artificial intelligence, we can develop an understanding of the changes that are occurring in bioinformatics, and how these changes are likely to influence the bioinformatics job market.
    • Biological and biochemical characterisation of purine analogue resistant clones of V79 Chinese hamster cells.

      Fox, Margaret; Boyle, John M; Fox, Brian W; Paterson Laboratories, Christie Hospital, Holt Radium Institute, Manchester M20 9BX, United Kingdom. (1976-06)
      Purine analogue resistant clones have been selected from the closely related Chinese hamster lines V79A and V79S. Clones were of either spontaneous origin or induced by EMS or ultraviolet light. The majority of clones selected in 8-azaguanine showed stable cross resistance to 6-thioguanine. Clones derived from V79A and selected for 6-thioguanine resistance were cross resistant to 8-azaguanine: however a group of 6-thioguanine resistant mutants selected from V79S cells were 8-azaguanine sensitive. All clones except two were unable to grow in HAT medium. The two exceptions were 8-azaguanine resistant, showed partial sensitivity to 6-thioguanine, and also differed in other biochemical characteristics. HGPRT activity was measurable in extracts of all clones under standard conditions. In many clones, HGPRT activity increased as the hypoxanthine concentration was reduced. Whole cell uptake of [14C] hypoxanthine was low in all cases examined and was not modified by incubation in the presence of amethopterin. The heat sensitivity and electrophoretic mobility of HGPRT in extracts of some clones was compared to that in wild-type extracts. All clones tested except one, which was consistently HAT positive, showed enhanced heat sensitivity and reduced electrophoretic mobility. None of the mutants reverted spontaneously at detectable frequency but some could be induced to revert by EMS. The presence of measurable enzyme with altered properties in all clones suggests that these revertable drug resistant clones represent missense mutants.
    • Biological and structural properties of MIP-1 alpha expressed in yeast.

      Clements, J M; Craig, S; Gearing, A J; Hunter, M G; Heyworth, Clare M; Dexter, T Michael; Lord, Brian I; British Bio-technology, Cowley, Oxford. (1992-01)
      The murine macrophage inflammatory proteins-1 alpha (MIP-1 alpha) and MIP-1 beta are distinct but closely related cytokines. Partially purified mixtures of the two proteins affect neutrophil function and cause local inflammation and fever. The particular properties of MIP-1 alpha have not been well studied, although it has been identified as being identical to an inhibitor of haemopoietic stem cell growth. We have expressed MIP-1 alpha in yeast cells and purified it to sequence homogeneity. Structural analysis of this biologically active material by circular dichroism and fluorescence spectroscopy confirms that MIP-1 alpha has a very similar secondary and tertiary structure to platelet factor 4 and interleukin 8 with which it shares limited sequence homology. The in-vitro stem cell inhibitory properties have been confirmed using a range of murine progenitor cells including purified bone marrow progenitor cells (FACS-1), the FDCP-mix A4 cell line, and spleen colony forming unit (CFU-S) populations. Plateau levels of inhibition of stem cell growth were achieved using concentrations of 0.15 micrograms/ml MIP-1 alpha. We have also demonstrated that MIP-1 alpha is active in vivo: 5 micrograms of MIP-1 alpha per mouse given as a bolus injection, protects stem cells from subsequent in-vitro killing by tritiated thymidine. MIP-1 alpha was also shown to enhance the proliferation of more committed progenitor granulocyte macrophage-colony forming cells (GM-CFC) in response to granulocyte macrophage-colony stimulating factor (GM-CSF).
    • Biological characteristics of cells migrating into the bloodstream.

      Testa, Nydia G; Cancer Research Campaign Department of Experimental Haematology, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, UK. (1996-03)
    • Biological characterization of recombinant vaccinia viruses in mice infected by the respiratory route.

      Williamson, J D; Reith, R W; Jeffrey, L J; Arrand, John R; Mackett, Mike; Department of Medical Microbiology, St Mary's Hospital Medical School, London, U.K. (1990-11)
      A murine model based on infection by the respiratory route has been used to study the pathogenesis of recombinant vaccinia viruses. The neurovirulent Western Reserve (WR) strain and the Wyeth smallpox vaccine strain were used as vectors. Recombinant viruses were constructed by insertion of the Epstein-Barr virus membrane glycoprotein 340 gene into the thymidine kinase (TK) gene of each vaccinia virus. Intranasal inoculation of DBA/2 mice with 10(6) pock-forming units (pk.f.u.) of the WR strain was lethal but mice survived similar infection with the WR recombinant virus. Each virus was recovered from lung, blood and brain but, unlike wild-type virus, the recombinant virus was subsequently cleared. No deaths occurred after similar infection with the Wyeth strain or the Wyeth recombinant virus. There was limited growth of the Wyeth strain in the respiratory tract, low levels of virus in the blood and only sporadic recovery in brain extracts. The Wyeth recombinant virus was cleared rapidly with little viraemia or detectable infection of the central nervous system. No phenotypic character determined in vitro could be related consistently to the virulence of wild-type and recombinant viruses. Although the lethal character of the WR strain was affected by its TK+ phenotype, mice survived infection by intranasal inoculation with 10(6) pk.f.u. of WR TK+ recombinant viruses which either expressed the human interleukin 2 gene or had a deficient vaccinia virus growth factor gene.
    • Biological consequences of p160v-abl protein tyrosine kinase activity in a primitive, multipotent haemopoietic cell line.

      Spooncer, Elaine; Fairbairn, Leslie J; Cowling, Graham J; Dexter, T Michael; Whetton, Anthony D; Owen-Lynch, P Jane; Department of Experimental Haematology, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, UK. (1994-04)
      A temperature sensitive abl protein tyrosine kinase gene was transferred into a multipotent haemopoietic stem cell line, and the primary biological effects of expression of the gene were examined at the permissive and non-permissive temperatures. Unlike previous studies in factor-dependent cell lines, we found that expression of the functional abl protein tyrosine kinase did not lead to growth autonomy. Furthermore, the cells were still able to undergo terminal myeloid differentiation. However, expression of the functional gene did lead to a delay in maturation with a concomitant increase in cell production, had a modest effect in terms of delayed apoptosis particularly when the cells were maintained at a high cell density, and slightly increased the response to sub-optimal concentrations of IL-3. In many respects, therefore, the effects of abl protein tyrosine kinase in these cells mimics the effect of bcr/abl in primary haemopoietic cells where growth factor independence and an aberrant differentiation profile are relatively late events in clonal evolution and are not intermediate consequences of activation of the abl gene.
    • Biological effect of silver-modified nanostructured titanium dioxide in cancer

      Lagopati, N.; Kotsinas, A.; Veroutis, D.; Evangelou, K.; Papaspyropoulos, A.; Arfanis, M.; Falaras, P.; Kitsiou, P. V.; Pateras, I.; Bergonzini, A.; et al. (2021)
      Background/aim: Nanomedicine is a promising scientific field that exploits the unique properties of innovative nanomaterials, providing alternative solutions in diagnostics, prevention and therapeutics. Titanium dioxide nanoparticles (TiO2 NPs) have a great spectrum of photocatalytic antibacterial and anticancer applications. The chemical modification of TiO2 optimizes its bioactive performance. The aim of this study was the development of silver modified NPs (Ag/TiO2 NPs) with anticancer potential. Materials and methods: Ag/TiO2 NPs were prepared through the sol-gel method, were fully characterized and were tested on cultured breast cancer epithelial cells (MCF-7 and MDA-MB-231). The MTT colorimetric assay was used to estimate cellular viability. Western blot analysis of protein expression along with a DNA-laddering assay were employed for apoptosis detection. Results and conclusion: We show that photo-activated Ag/TiO2 NPs exhibited significant cytotoxicity on the highly malignant MDA-MB-231 cancer cells, inducing apoptosis, while MCF-7 cells that are characterized by low invasive properties were unaffected under the same conditions.
    • Biological effects of stroma-derived factor-1 alpha on normal and CML CD34+ haemopoietic cells.

      Dürig, J; Rosenthal, C; Elmaagacli, A; Heyworth, Clare M; Halfmeyer, K; Kasper, Christoph; Novotny, J; Dührsen, U; Department of Haematology, University Hospital Essen, Germany. (2000-09)
      We compared the biological effects of the CXC chemokine SDF-1alpha on immunomagnetically purified CD34+ cells isolated from human normal bone marrow (NBM), leukapheresis products (LP) and patients with chronic myeloid leukaemia (CML). LP CD34+ cells showed a significantly stronger migration response to SDF-1alpha (100 ng/ml) than CD34+ cells isolated from the peripheral blood (PB) of CML patients (P < 0.05). The chemotactic response to SDF-1alpha was also reduced in CML BM CD34+ cells in comparison to NBM CD34+ cells but the observed differences were not statistically significant. In analogy to normal CD34+ cells circulating CML PB CD34+ cells were less responsive to SDF-1alpha than their BM counterparts (P < 0.05). Furthermore, SDF-1alpha elicited similar concentration-dependent growth suppressive effects on normal and CML CD34+ cells (P > 0.05) in colony-forming cell assays. We then demonstrated that SDF-1alpha triggers intracellular calcium increases in CD34+ cells and there were no differences in the time course and dose response characteristics of normal and CML CD34+ cells. The reduced migration response to SDF-1alpha in CML CD34+ cells was not due to a down-regulation of the SDF-1alpha receptor CXCR-4 as flow cytometric analysis revealed similar CXCR-4 expression levels on NBM, LP, CML PB and CML BM CD34+ cells (P > 0.05). Finally, no differences in the modulation of CXCR-4 levels in response to SDF-1alpha and serum were observed in CML and normal CD34+ cells. Our data suggest that the impaired chemotactic response of CML CD34+ cells to SDF-1alpha is not caused by a lack or complete uncoupling of CXCR-4, but may be due to an intracellular signalling defect downstream of the receptor.
    • Biological implications of the instability of the N-glycosidic bone of 3-methyldeoxyadenosine in DNA.

      Margison, Geoffrey P; O'Connor, Peter J; Paterson Laboratories, Christie Hospital and Holt Radium Institute, Manchester (1973-12-21)
    • Biological markers: maintaining standards

      Leake, Robin; Anderson, Elizabeth; Dowsett, Mitch; Iles, Ray; Nicholson, Robert I; Robertson, John F R; Walker, Rosemary (2000)
    • Biological mechanisms linking obesity and cancer risk: new perspectives.

      Roberts, Darren L; Dive, Caroline; Renehan, Andrew G; Clinical and Experimental Pharmacology, Paterson Institute for Cancer Research, The Christie NHS Foundation Trust, Manchester, UK. (2010)
      Body mass index, as an approximation of body adiposity, is associated with increased risk of several common and less common malignancies in a sex- and site-specific manner. These findings implicate sex- and cancer site-specific biological mechanisms underpinning these associations, and it is unlikely that there is a "one system fits all" mechanism. Three main candidate systems have been proposed-insulin and the insulin-like growth factor-I axis, sex steroids, and adipokines-but there are shortfalls to these hypotheses. In this review, three novel candidate mechanisms are proposed: obesity-induced hypoxia, shared genetic susceptibility, and migrating adipose stromal cells. While public health policies aimed at curbing the underlying causes of the obesity epidemic are being implemented, there is a parallel need to better understand the biological processes linking obesity and cancer as a prerequisite to the development of new approaches to prevention and treatment.
    • Biological optimization for mediastinal lymphoma radiotherapy - a preliminary study

      Rechner, LA; Modiri, A; Stick, LB; Maraldo, MV; Aznar, Marianne Camille; Rice, SR; Sawant, A; Bentzen, SM; Vogelius, IR; Specht, L; et al. (2020)
    • Biological relevance of cell-in-cell in cancers

      Mackay, HL; Muller, Patricia; Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham B15 2TT, U.K (2019)
      Cell-in-cell (CIC) is a term used to describe the presence of one, usually living, cell inside another cell that is typically considered non-phagocytic. Examples of this include tumour cells inside tumour cells (homotypic), mesenchymal stem cells inside tumour cells (heterotypic) or immune cells inside tumour cells (heterotypic). CIC formation can occur in cell lines and in tissues and it has been most frequently observed during inflammation and in cancers. Over the past 10 years, many researchers have studied CIC structures and a few different models have been proposed through which they can be formed, including entosis, cannibalism and emperipolesis among others. Recently, our laboratory discovered a role for mutant p53 in facilitating the formation of CIC and promoting genomic instability. These data and research by many others have uncovered a variety of molecules involved in CIC formation and have started to give us an idea of why they are formed and how they could contribute to oncogenic processes. In this perspective, we summarise current literature and speculate on the role of CIC in cancer biology.
    • Biological Response Modifiers and Normal Tissue Injury After Irradiation.

      Hendry, Jolyon H; The Cancer Research Campaign Department of Experimental Radiation Oncology, Paterson Institute for Cancer Research, Manchester, England (1994-04)
      The reactions of tissues after irradiation can be modified using a variety of biologically based approaches. Cellular radiosensitivity can be changed using growth regulatory molecules (GRM) that have cell-cycle-mediated effects. Radiosensitivity can also be changed using prostaglandins, dose-miodifying factors of up to around 2 can be achieved. Proliferation and differentiation of precursor cells in early-reacting tissues can be promoted by GRM, producing substantial dose-modifying factors in tissues (eg, up to around 2 for marrow failure). Enhanced cell migration probably also plays an important role in the response of epithelial and stromal tissue elements. Antibiotics can prevent or delay the onset of bacterial infection in susceptible tissues (eg, marrow and intestine) to allow time for tissue recovery to occur. Even in situations where injury is already developing, a choice of dietary components in the case of kidney injury or modifiers of the vasculature in general (eg, using essential fatty acids) can delay or reduce the onset of late injury. Biological response modifiers have the potential to attain an increasingly important role in the management of cancer patients receiving radiotherapy as well as in the infrequent cases of high doses received in accidents.
    • Biology and clinical relevance of circulating tumour cells.

      Carter, Louise; Metcalf, Robert; Blackhall, Fiona H; Dive, Caroline; Krebs, Matthew G; Clinical and Experimental Pharmacology Group, Paterson institute for Cancer Research, Manchester, UK; (2012-10)
    • Biology of BCR-ABL.

      Chopra, Rajesh; Pu, Qingqiu; Elefanty, A G; Christie Hospital and Paterson Institute for Cancer Research, Manchester, UK. (1999-12)
    • Biology of blood progenitor cells used in transplantation.

      Pettengell, Ruth; Testa, Nydia G; CRC Department of Medical Oncology, Christie Hospital, Manchester, UK. (1995-01)
      Blood progenitor cells (BPC) are increasingly used in a variety of clinical settings. These include autologous and allogeneic transplantation after myeloablative therapy, and gene therapy. The optimal blood products for each of these applications have not been defined. The use of different cytotoxic drugs and cytokines, alone and in combination, results in the mobilisation of different total numbers and relative proportions of primitive and committed BPC. Some cytotoxics and cytokines not only are poor at mobilising BPC, but also are myelotoxic. Here we review the biology of BPC mobilisation and its implications for their clinical use.
    • The biology of long-term bone marrow cultures and its application to bone marrow transplantation.

      Testa, Nydia G; Dexter, T Michael; Paterson Institute for Cancer Research, Christie Hospital, Manchester, UK. (1991-04)
      Long-term bone marrow cultures have been applied to the study and to the treatment of hemopoietic disease. The incidence of murine primitive (stem) cells with the ability to repopulate irradiated bone morrow stroma is similar to that of cells able to repopulate the hemopoietic system of potentially lethally irradiated mice. In human bone marrow, cells with in vitro repopulating ability have been estimated as 0.5% to 1% of the CD34+ cells. The increase in primitive cells in the circulation seen after administration of growth factors has been exploited by harvesting those cells for use together with bone marrow in autologous transplants. The ability of primitive cells (harvested after granulocyte colony-stimulating factor plus chemotherapy) to reconstitute irradiated marrow stromas indicates that their repopulation capacity in vitro is at least as good as that of bone marrow. This is confirmed by experimental data in mice showing that small volumes of peripheral blood (after granulocyte colony-stimulating factor administration) are capable of long-term repopulation. The regulator capacity of marrow stroma has been exploited to purge bone marrow cultures from patients with acute myeloblastic leukemia in first remission and from treated patients with chronic myelogenous leukemia before using the cultured cells for autologous transplant. The results to date, although preliminary, indicate a role for this methodology in the treatment of leukemia.
    • The biology of photodynamic therapy.

      Moore, James V; West, Catharine M L; Whitehurst, Colin; Laser Oncology Programme, Paterson Institute for Cancer Research, Christie Hospital (NHS) Trust, Manchester, UK. (1997-05)
      The subcellular, cellular and tissue/tumour interactions with non-toxic photosensitizing chemicals plus non-thermal visible light (photodynamic therapy (PDT) are reviewed. The extent to which endothelium/vasculature is the primary target is discussed, and the biochemical opportunities for manipulating outcome highlighted. The nature of tumour destruction by PDT lends itself to imaging outcome by MRI and PET.
    • Biomarker method validation in anticancer drug development.

      Cummings, Jeffrey; Ward, Timothy H; Greystoke, Alastair; Ranson, Malcolm R; Dive, Caroline; Clinical and Experimental Pharmacology, Paterson Institute for Cancer Research, University of Manchester, Manchester, UK. jcummings@picr.man.ac.uk (2008-02)
      Over recent years the role of biomarkers in anticancer drug development has expanded across a spectrum of applications ranging from research tool during early discovery to surrogate endpoint in the clinic. However, in Europe when biomarker measurements are performed on samples collected from subjects entered into clinical trials of new investigational agents, laboratories conducting these analyses become subject to the Clinical Trials Regulations. While these regulations are not specific in their requirements of research laboratories, quality assurance and in particular assay validation are essential. This review, therefore, focuses on a discussion of current thinking in biomarker assay validation. Five categories define the majority of biomarker assays from 'absolute quantitation' to 'categorical'. Validation must therefore take account of both the position of the biomarker in the spectrum towards clinical end point and the level of quantitation inherent in the methodology. Biomarker assay validation should be performed ideally in stages on 'a fit for purpose' basis avoiding unnecessarily dogmatic adherence to rigid guidelines but with careful monitoring of progress at the end of each stage. These principles are illustrated with two specific examples: (a) absolute quantitation of protein biomarkers by mass spectrometry and (b) the M30 and M65 ELISA assays as surrogate end points of cell death.