• Obesity and hepatosteatosis in mice with enhanced oxidative DNA damage processing in mitochondria.

      Zhang, H; Xie, C; Spencer, H; Zuo, C; Higuchi, M; Ranganathan, G; Kern, P; Chou, M; Huang, Q; Szczesny, B; et al. (2011-04)
      Mitochondria play critical roles in oxidative phosphorylation and energy metabolism. Increasing evidence supports that mitochondrial DNA (mtDNA) damage and dysfunction play vital roles in the development of many mitochondria-related diseases, such as obesity, diabetes mellitus, infertility, neurodegenerative disorders, and malignant tumors in humans. Human 8-oxoguanine-DNA glycosylase 1 (hOGG1) transgenic (TG) mice were produced by nuclear microinjection. Transgene integration was analyzed by PCR. Transgene expression was measured by RT-PCR and Western blot analysis. Mitochondrial DNA damage was analyzed by mutational analyses and measurement of mtDNA copy number. Total fat content was measured by a whole-body scan using dual-energy X-ray absorptiometry. The hOGG1 overexpression in mitochondria increased the abundance of intracellular free radicals and major deletions in mtDNA. Obesity in hOGG1 TG mice resulted from increased fat content in tissues, produced by hyperphagia. The molecular mechanisms of obesity involved overexpression of genes in the central orexigenic (appetite-stimulating) pathway, peripheral lipogenesis, down-regulation of genes in the central anorexigenic (appetite-suppressing) pathway, peripheral adaptive thermogenesis, and fatty acid oxidation. Diffuse hepatosteatosis, female infertility, and increased frequency of malignant lymphoma were also seen in these hOGG1 TG mice. High levels of hOGG1 expression in mitochondria, resulting in enhanced oxidative DNA damage processing, may be an important factor in human metabolic syndrome, infertility, and malignancy.
    • Observations on the settling and recoverability of transplanted hemopoietic colony-forming units in the mouse spleen.

      Lord, Brian I; Hendry, Jolyon H; Paterson Laboratories, Christie Hospital and Holt Radium Institute, Manchester M20 9BX, England (1973-03)
    • Occupational exposure in medicine--a review of radiation doses to hospital staff in north-west England.

      Hughes, J S; Roberts, G C; Stephenson, S K; National Radiological Protection Board, Chilton, Didcot, Oxon (1983-10)
      The personal monitoring service operated by the Regional Physics Department at the Christie Hospital and Holt Radium Institute, Manchester, monitors staff involved with the uses of ionising radiations at all hospitals and clinics administered by the North Western Region Health Authority in England. Monitoring results relating principally to exposure during 1981 have been collated and examined. The analysis indicates that the doses received by staff are for the most part very low and provide little reason for concern. The only area of work in which worthwhile and cost-effective dose reductions could probably be achieved is that involving the use of pre-loaded applicators in gynaecological intra-cavitary therapy. Some relatively high staff exposures result from the use of this technique, and very significant reductions in these doses are confidently expected from a programme which has now commenced for the increasing use of remotely-controlled after-loading equipment housed in shielded treatment rooms.
    • Oesophagus exposure in breast cancer radiotherapy: systematic review of oesophageal doses 2010-2020

      Duane, F.; Kerr, A.; Aznar, Marianne Camille; Wang, Z.; Ntentas, G.; Darby, S.; Taylor, C.; Radiation Oncology, St Luke's Radiation Oncology Network, Dublin, Ireland; (2021)
      Purpose or Objective Breast cancer radiotherapy has been shown to increase the risk of subsequent primary oesophageal cancer. It is unclear if avoidance of the oesophagus is being considered routinely during radiotherapy treatment planning. This study aims to describe exposure of the oesophagus from modern breast cancer regimens. Materials and Methods A systematic review of oesophageal doses from breast cancer radiotherapy regimens published 2010-2020 was undertaken. Average mean oesophageal doses and average maximum oesophageal doses were described for different anatomical regions irradiated and techniques used. Oesophageal exposure from current modern regimens was compared to that received in previous decades. Results 112 regimens from 18 countries reporting oesophagus doses were identified. The average mean oesophagus dose was 0.2 Gy (range 0.1-0.4) for partial breast irradiation, 2.7 Gy (range 0.1-16.6) for whole breast/chest wall radiotherapy and 11.4 Gy (range 0.0–31.9) with the addition of regional nodal irradiation. For regimens that included regional nodal irradiation, the average mean oesophageal dose was higher for IMRT (17.5 Gy static IMRT, 12.5 Gy rotational IMRT) than tangential radiotherapy (7.5 Gy) (p < 0.001). Overall, average oesophageal exposure from modern regimens was similar to that estimated from regimens used in previous decades. Conclusion Exposure of the oesophagus remains an issue in modern breast cancer radiotherapy particularly for patients undergoing IMRT. Routine avoidance of the oesophagus during treatment planning may reduce the number of women developing a subsequent primary oesophageal cancer in the future.
    • Oestrogens, Beatson and endocrine therapy

      Howell, Anthony; Clarke, Robert B; Anderson, Elizabeth (1997)
    • Of hemangioblast, hemogenic endothelium and primitive versus definitive hematopoiesis.

      Lacaud, Georges; Kouskoff, Valerie; Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow road (2016-12-30)
      The types of progenitors generated during the successive stages of embryonic blood development are now fairly well characterized. The terminology used to describe these waves, however, can still be confusing. What is truly primitive? What is uniquely definitive? These questions become even more challenging to answer when blood progenitors are derived in vitro upon the differentiation of embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs). Similarly, the cellular origin of these blood progenitors can be controversial. Are all blood cells, including the primitive wave, derived from hemogenic endothelium? Is the hemangioblast an in vitro artefact or is this mesoderm entity also present in the developing embryo? Here we discuss the latest findings and propose some consensus relating to these controversial issues.
    • OGO: an ontological approach for integrating knowledge about orthology.

      Miñarro-Gimenez, Jose Antonio; Madrid, Marisa; Fernandez-Breis, Jesualdo Tomas; Departamento de Informática y Sistemas, Universidad de Murcia, Murcia, 30100, Spain. jose.minyarro@um.es (2009)
      BACKGROUND: There exist several information resources about orthology of genes and proteins, and there are also systems for querying those resources in an integrated way. However, caveats with current approaches include lack of integration, since results are shown sequentially by resource, meaning that there is redundant information and the users are required to combine the results obtained manually. RESULTS: In this paper we have applied the Ontological Gene Orthology approach, which makes use of a domain ontology to integrate the information output from selected orthology resources. The integrated information is stored in a knowledge base, which can be queried through semantic languages. A friendly user interface has been developed to facilitate the search; consequently, users do not need to have knowledge on ontologies or ontological languages to obtain the relevant information. CONCLUSION: The development and application of our approach allows users to retrieve integrated results when querying orthology information, providing a gene product-oriented output instead of a traditional information resource-oriented one. Besides this benefit for users, it also allows a better exploitation and management of orthology information and knowledge.
    • ogt alkyltransferase enhances dibromoalkane mutagenicity in excision repair-deficient Escherichia coli K-12.

      Abril, N; Luque-Romero, F L; Prieto-Alamo, M J; Margison, Geoffrey P; Pueyo, C; Departamento de Genética, Facultad de Ciencias, Universidad de Córdoba, Espana. (1995-02)
      We examined the role of the O6-alkylguanine-DNA alkyltransferase encoded by ogt gene in the sensitivity of Escherichia coli to the mutagenic effects of the dibromoalkanes, dibromoethane and dibromomethane, by comparing responses in ogt- bacteria to those in their isogenic ogt+ parental counterparts. The effects of the uvrABC excision-repair system, the adaptive response, mucAB and umuDC mutagenic processing, and glutathione bioactivation on the differential responses of ogt- and ogt+ bacteria were also studied. Mutation induction was monitored by measuring the frequency of forward mutations to L-arabinose resistance. Induced mutations occurred only in excision repair-defective strains and were totally (with dibromomethane) or substantially (with dibromoethane) dependent on the alkyltransferase (ATase) encoded by the ogt gene. An increased mutagenic response to both dibromoalkanes was also seen in ogt- bacteria that overexpressed the ogt protein from a multicopy plasmid, indicating that the differences in mutability between ogt+ and ogt- bacteria were not dependent on the ogt- null allele carried by the defective strain. The ATase encoded by the constitutive ogt gene was more effective in promoting dibromoalkane mutagenicity than the ada ATase induced by exposure to low doses of a methylating agent. The mutagenicity promoted by the ogt ATase was dependent on both glutathione bioactivation and SOS mutagenic processing. To our knowledge, this paper presents for the first time evidence that DNA ATases, in particular the ATase encoded by the ogt gene, can increase the mutagenic effects of a DNA-damaging agent. The mechanism of this effect has yet to be established.
    • Oligomeric self-association contributes to E2A-PBX1-mediated oncogenesis

      Lin, CH; Wang, Z; Duque-Afonso, J; Wong, SH; Demeter, J; Loktev, AV; Somervaille, Tim CP; Jackson, PK; Cleary, ML; Department of Pathology, Stanford University School of Medicine, Stanford, CA, 94305, USA (2019)
      The PBX1 homeodomain transcription factor is converted by t(1;19) chromosomal translocations in acute leukemia into the chimeric E2A-PBX1 oncoprotein. Fusion with E2A confers potent transcriptional activation and constitutive nuclear localization, bypassing the need for dimerization with protein partners that normally stabilize and regulate import of PBX1 into the nucleus, but the mechanisms underlying its oncogenic activation are incompletely defined. We demonstrate here that E2A-PBX1 self-associates through the PBX1 PBC-B domain of the chimeric protein to form higher-order oligomers in t(1;19) human leukemia cells, and that this property is required for oncogenic activity. Structural and functional studies indicate that self-association facilitates the binding of E2A-PBX1 to DNA. Mutants unable to self-associate are transformation defective, however their oncogenic activity is rescued by the synthetic oligomerization domain of FKBP, which confers conditional transformation properties on E2A-PBX1. In contrast to self-association, PBX1 protein domains that mediate interactions with HOX DNA-binding partners are dispensable. These studies suggest that oligomeric self-association may compensate for the inability of monomeric E2A-PBX1 to stably bind DNA and circumvents protein interactions that otherwise modulate PBX1 stability, nuclear localization, DNA binding, and transcriptional activity. The unique dependence on self-association for E2A-PBX1 oncogenic activity suggests potential approaches for mechanism-based targeted therapies.
    • Oligosaccharide mapping and sequence analysis of glycosaminoglycans.

      Turnbull, Jeremy E; Department of Medical Oncology, University of Manchester, Christie Hospital and Holt Radium Institute, UK. (1993)
    • Oligosaccharide mapping of heparan sulphate by polyacrylamide-gradient-gel electrophoresis and electrotransfer to nylon membrane.

      Turnbull, Jeremy E; Gallagher, John T; Department of Clinical Research, University of Manchester, Christie Hospital and Holt Radium Institute, U.K. (1988-04-15)
      A new method that we have called 'oligosaccharide mapping' is described for the analysis of radiolabelled heparan sulphate and other glycosaminoglycans. The method involves specific enzymic or chemical scission of polysaccharide chains followed by high-resolution separation of the degradation products by polyacrylamide-gradient-gel electrophoresis. The separated oligosaccharides are immobilized on charged nylon membranes by electrotransfer and detected by fluorography. A complex pattern of discrete bands is observed covering an oligosaccharide size range from degree of polymerization (d.p.) 2 (disaccharide) to approximately d.p. 40. Separation is due principally to differences in Mr, though the method also seems to detect variations in conformation of oligosaccharide isomers. Resolution of oligosaccharides is superior to that obtained with isocratic polyacrylamide-gel-electrophoresis systems or gel chromatography, and reveals structural details that are not accessible by other methods. For example, in this paper we demonstrate a distinctive repeating doublet pattern of iduronate-rich oligosaccharides in heparitinase digests of mouse fibroblast heparan sulphate. This pattern may be a general feature of mammalian heparan sulphates. Oligosaccharide mapping should be a valuable method for the analysis of fine structure and sequence of heparan sulphate and other complex polysaccharides, and for making rapid assessments of the molecular distinctions between heparan sulphates from different sources.
    • Oligosaccharides as anti-angiogenic agents.

      Cole, Claire L; Jayson, Gordon C; Translational Angiogenesis Group, Paterson Institute for Cancer Research, Wilmslow Road, Withington, Manchester M20 4BX, UK. ccole@picr.man.ac.uk (2008-03)
      BACKGROUND: Several studies of drugs that inhibit tumour angiogenesis have shown improvements in the survival of cancer patients, thus validating angiogenesis as a clinically relevant target. Both intracellular and extracellular approaches have shown promising results in clinical situations. OBJECTIVES: To compare and contrast oligosaccharide therapies and other anti-angiogenic compounds for their benefits and toxicity. Methods: Analysis of the relevant literature including presentations at recent conferences. RESULTS: Receptor tyrosine kinase inhibitors are orally available but have a broad spectrum of activity which is associated with toxicity. Antibodies are associated with different toxicities, however, they are administered parenterally. Oligosaccharides that act as competitive inhibitors of heparan sulfate (HS) are in the early and late phases of clinical development. The advantage of oligosaccharides should be that they can be designed to target several angiogenic molecules, that they are relatively safe and that they can be administered subcutaneously at home. The key questions concerning their development focus on whether compounds with sufficient affinity and relative specificity can be generated, whether they are active at doses that do not perturb the coagulation cascade to a clinically dangerous level, whether the synthetic routes are scalable and, whether the current Phase III trials will yield positive results. CONCLUSIONS: Saccharides represent a novel and exciting therapeutic approach that targets a spectrum of angiogenic molecules that cannot be inhibited through established drug development programmes.
    • Omega-3 fatty acid intake and decreased risk of skin cancer in organ transplant recipients

      Miura, K.; Way, M.; Jiyad, Z.; Marquart, L.; Plasmeijer, E. I.; Campbell, S.; Isbel, N.; Fawcett, J.; Ferguson, L. E.; Davis, M.; et al. (2020)
      Purpose: Organ transplant recipients have over 100-fold higher risk of developing skin cancer than the general population and are in need of further preventive strategies. We assessed the possible preventive effects of omega-3 polyunsaturated fatty acid (PUFA) intake from food on the two main skin cancers, squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) in kidney and liver transplant recipients. Methods: Adult kidney or liver transplant recipients transplanted for at least 1 year and at high risk of skin cancer were recruited from the main transplant hospital in Queensland, 2012-2014 and followed until mid-2016. We estimated their dietary total long-chain omega-3 PUFAs and α-linolenic acid intakes at baseline using a food frequency questionnaire and ranked PUFA intakes as low, medium, or high. Relative risks (RRsadj) of skin cancer adjusted for confounding factors with 95% confidence intervals (CIs) were calculated. Results: There were 449 transplant recipients (mean age, 55 years; 286 (64%) male). During follow-up, 149 (33%) patients developed SCC (median 2/person; range 1-40) and 134 (30%), BCC. Transplant recipients with high total long-chain omega-3 PUFA compared with low intakes showed substantially reduced SCC tumour risk (RRadj 0.33, 95% CI 0.18-0.60), and those with high α-linolenic acid intakes experienced significantly fewer BCCs (RRadj 0.40, 95% CI 0.22-0.74). No other significant associations were seen. Conclusion: Among organ transplant recipients, relatively high intakes of long-chain omega-3 PUFAs and of α-linolenic acid may reduce risks of SCC and BCC, respectively.
    • Omega-3 fatty acid supplement skin cancer prophylaxis in lung transplant recipients: A randomized, controlled pilot trial

      Miura, K; Vail, A; Chambers, D; Hopkins, PM; Ferguson, L; Grant, M; Rhodes, LE; Green, Adèle C; Cancer and Population Studies Group, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia (2018)
      BACKGROUND: Lung transplant recipients (LTRs) are at very high risk of skin cancer. Omega-3 fatty acids (FAs) are anti-inflammatory and immune-modulating and could potentially reduce this risk. We assessed the feasibility of omega-3 FA supplementation to reduce skin cancer among these patients. METHODS: LTRs aged 18+ years, at least 1 year post-transplant, were recruited from the outpatient clinic of The Prince Charles Hospital, Brisbane. Participants were randomly allocated to 4-times-daily supplements containing either omega-3 FA (3.36 eicosapentaenoic acid [EPA]?+?docosahexaenoic acid) or placebo (4 g olive oil) for 12 months. Primary outcomes were rates of recruitment, retention, adherence (assessed by plasma omega-3 FA), and safety. Secondary outcomes were incident skin cancers. RESULTS: Among 106 eligible lung transplant recipients, 49 consented to take part (46%) with 25 allocated to omega-3 FA and 24 to placebo supplements. Of these, 22 (88%) and 20 (83%), respectively, completed the trial. After 12 months, median plasma EPA increased substantially in the intervention group (125.0 to 340.0 �mol/L), but not the placebo group (98.0 to 134.5 �mol/L). In the intervention group, 6 patients developed skin cancers compared with 11 in the placebo group, giving an odds ratio (95% confidence interval) of 0.34 (0.09 to 1.32). There were no serious, active intervention-related adverse events. CONCLUSIONS: This pilot trial among LTRs showed acceptable recruitment and high retention and adherence. We demonstrated a signal for reduction of new skin cancer cases in those taking omega-3 FA supplements, which supports the notion that a larger, more definitive trial is warranted.
    • On Target 2: updated guidance for image-guided radiotherapy

      McNair, H. A.; Franks, K. N.; van Herk, Marcel; Royal Marsden NHS Foundation Trust, Sutton, UK; Institute of Cancer Research, London, UK (2021)
    • On the mechanism of hyperthermia-induced BRCA2 protein degradation.

      van den Tempel, N; Zelensky, AN; Odijk, H; Laffeber, C; Schmidt, Christine K; Brandsma, I; Demmers, J; Krawczyk, PM; Kanaar, R; Department of Molecular Genetics, Oncode Institute, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands (2019)
      The DNA damage response (DDR) is a designation for a number of pathways that protects our DNA from various damaging agents. In normal cells, the DDR is extremely important for maintaining genome integrity, but in cancer cells these mechanisms counteract therapy-induced DNA damage. Inhibition of the DDR could therefore be used to increase the efficacy of anti-cancer treatments. Hyperthermia is an example of such a treatment-it inhibits a sub-pathway of the DDR, called homologous recombination (HR). It does so by inducing proteasomal degradation of BRCA2 -one of the key HR factors. Understanding the precise mechanism that mediates this degradation is important for our understanding of how hyperthermia affects therapy and how homologous recombination and BRCA2 itself function. In addition, mechanistic insight into the process of hyperthermia-induced BRCA2 degradation can yield new therapeutic strategies to enhance the effects of local hyperthermia or to inhibit HR. Here, we investigate the mechanisms driving hyperthermia-induced BRCA2 degradation. We find that BRCA2 degradation is evolutionarily conserved, that BRCA2 stability is dependent on HSP90, that ubiquitin might not be involved in directly targeting BRCA2 for protein degradation via the proteasome, and that BRCA2 degradation might be modulated by oxidative stress and radical scavengers.
    • On the nature of the active component of haematoporphyrin 'derivative'.

      Land, Edward J; Redmond, R; Truscott, T G; Paterson Laboratories, Christie Hospital, Manchester M20 9BX UK (1986-08)
      The active component of the photochemotherapeutic drug 'haematoporphyrin derivative' was studied by laser flash photolysis. The triplet extinction coefficient of this species was determined using a method in which the calculated value is dependent on the assumed molecular weight. This value was then incorporated in the evaluation of the quantum yield of triplet by a comparative technique. Since the maximum possible value of this yield is unity, it is shown that the molecular weight of the active component is greater than or equal to 3000, so that, on average, the drug molecule must contain at least 5 porphyrin units.
    • On the photosensitizing properties of n-formylkynurenine and related compounds.

      Pileni, Marie-Paule; Santus, René; Land, Edward J; Paterson Laboratories, Christie Hospital and Holt Radium Institute, Manchester (1978)
    • On the sensitisation of skin radionecrosis in mice by misonidazole at low doses.

      Hendry, Jolyon H; Sutton, M L; Paterson Laboratories, Christie Hospital and Holt Radium Institute, Wilmslow Road, Withington, Manchester M20 9BX, UK (1984-06)
      The sensitisation by misonidazole of tail radionecrosis in mice has been assessed using single doses from 0.01 to 1 mg g-1 body weight, for tails in three different states of oxygenation affecting sensitivity. The levels of sensitisation after different injected doses of misonidazole could be described reasonably well by the Alper -Howard-Flanders relationship, originally applied to the sensitisation of cells by oxygen, and hence the relationship could be used for interpolation. With clamped tails gassed with nitrogen at room temperature, 21-25 degrees C, the injected dose giving half the maximum sensitisation (defined as K inj ) was about 0.12-0.17 mg g-1 (0.6-0.8 mM). Unclamped tails in air demonstrated a value for K inj of about 0.14 mg g-1, indicating that the background level of oxygen and the injected misonidazole were not additive regarding sensitisation. With clamped tails gassed with nitrogen warmed to 37 degrees C (near body-core temperature) the sensitivity was slightly increased compared with clamped tails at 21-25 degrees C, and the additional increase in sensitivity following injections of misonidazole ( K inj of about 0.22 mg g-1) was less than at 21-25 degrees. With tails in air at 37 degrees C the increase in sensitivity following misonidazole was much more marked ( K inj of about 0.05 mg g-1) than expected. When eight "daily" fractions were given using 0.67 mg g-1 misonidazole and with the target cells well oxygenated at 37 degrees C (effective OER of about 2.0), the amount of sensitisation was less than for single doses, but it was similar (i.e. dose-modifying) for radiation doses per fraction between 2.6 and 6.3 Gy. At a dose of 0.1 mg g-1, giving a serum level corresponding to about the maximum tolerable in humans, the dose reduction factor would be only about 1.03 which corresponds roughly to a doubling in the tail necrosis rate from 5% to 10%. With future less neurotoxic drugs, higher serum levels may be expected to be tolerated and hence the dose reduction factor could be greater. This aspect, applicable to some but not all tissues tested in mice, should not be neglected in the design of future clinical trials with hypoxic-cell radiosensitisers .