• Triplet state properties and triplet-state-oxygen interactions of some linear and angular furocoumarins.

      Knox, C N; Land, Edward J; Truscott, T G; Department of Chemistry, Paisley College, UK. (1988-03)
      Linear and angular furocoumarins with conjugated external carbonyl substituents show higher triplet and singlet oxygen yields than the corresponding unsubstituted molecules. The efficiency of the oxygen quenching process to yield singlet oxygen is also higher for these substituted molecules. These changes are interpreted in terms of the "proximity effect" associated with two nearly degenerate n pi* and pi pi* excited states, and variations in the excess energy following furocoumarin triplet quenching by ground state triplet oxygen to yield singlet oxygen.
    • Triplet state properties of malonic acid C60 derivatives C60 [C(COOR)2]n; R=H, Et; n=16

      Bensasson, René V; Berberan-Santos, M N; Brettreich, M; Frederiksen, J; Gottinger, H; Hirsch, A; Land, Edward J; Leach, S; McGarvey, D J; Schonberger, H; et al. (2001)
    • Triplet state properties of N-mTEG[60]fulleropyrrolidine mono and bisadduct derivatives

      Kordatos, Konstantinos; Da Ros, Tatiana; Prato, Maurizio; Leach, Sydney; Land, Edward J; Bensasson, René V; Dipartimento di Scienze Farmaceutiche, Universita di Trieste, Piazzale Europa 1, 34127 Trieste, Italy (2001)
    • Triplet states of carotenoids from photosynthetic bacteria studied by nanosecond ultraviolet and electron pulse irradiation.

      Bensasson, R; Land, Edward J; Maudinas, B; ER 98 Laboratoire de Chimie Physique, Universite de Paris VI, 91405-Orsay, France (1976-03)
    • Triplet states of porphyrin esters.

      Bonnett, R; Charlambides, A; Land, Edward J; Sinclair, R; Tait, D; Truscott, T (1980)
    • Triplet, radical anion and radical cation spectra of furocoumarins.

      Bensasson, R V; Chalvet, O; Land, Edward J; Ronfard-Haret, J; Laboratoire de Biophysique, Inserm U.201, CNRS ERA 951, Museum National d'Histoire Naturelle, 61, Rue Buffon, 75005 Paris. (1984-03)
    • Triplet-states of ubiquinone analogs studied by ultraviolet and electron nanosecond irradiation

      Amouyal, E; Bensasson, R; Land, Edward J; ER98 Laboratoire de Chimie Physique, Universite de Paris VI, 91405-Orsay, France (1974)
    • Tritiated thymidine and bromodeoxyuridine double-labelling studies on growth factors and oral epithelial proliferation in the mouse.

      Thomson, P J; McGurk, Mark; Potten, Christopher S; Walton, G M; Appleton, D R; Oral and MaxilloFacial Surgery, The Dental School, Newcastle upon Tyne, UK. (1999-09)
      Mouse tongue epithelium is characterized by a circadian variation in the number of cells undergoing DNA synthesis. Groups of male BDF1 mice were followed over 48 h and a double-labelling method with tritiated thymidine and bromodeoxyuridine used to determine S-phase labelling indices, together with cell influx to and cell efflux from S, at 4-hourly time points. Control animals exhibited diurnal peaks in labelling index at 03:00 with trough activity 12 h later at 15:00. Cell influx peaked at 23:00 with troughs occurring between 11:00 to 15:00. Peak cell efflux occurred at 07:00 with trough activity at 19:00. Animals injected with epidermal growth factor at 05:00 demonstrated a significant fall in both influx and efflux throughout the 48-h period (P < 0.001), but with preservation of labelling indices, suggesting a slower transit of cells through S-phase, whereas epidermal growth factor injected at 15:00 only produced a significant rise in cell-efflux values. Adrenergic stimulation by intravenous phenylephrine/isoprenaline injection at both 05:00 and 15:00 resulted in a significant rise in cell efflux (P < 0.001), although there was also a rise in labelling index in the 15:00 group (P < 0.001). Animals injected with calmodulin at 05:00 demonstrated a significant reduction in labelling index throughout the 48-h period (P < 0.001), but maintained control values for cell influx and efflux, suggesting faster transit of cells through S. Calmodulin injection at 15:00 produced only a significant reduction in cell influx (P < 0.001). Administration of exogenous growth factors significantly alters the normal rhythmical proliferation of oral epithelial cells in a mouse model. These effects appear to be both growth factor- and time-dependent, and may have both physiological and pathological implications.
    • Trophoblast glycoprotein recognised by monoclonal antibody 5T4 maps to human chromosome 6q14-q15.

      Boyle, John M; Grzeschik, K H; Heath, P R; Morten, J E; Stern, Peter L; Department of Biochemical Genetics, Paterson Institute of Cancer Research, Christie Hospital and Holt Radium Institute, Manchester, UK. (1990-04)
      Human X rodent hybrids were stained by indirect immunofluorescence with 5T4, a murine monoclonal antibody that recognises a 72 kdalton glycoprotein expressed by human trophoblasts and a very restricted range of adult tissues; they were analysed by flow cytometry. Concordance analysis supported by segregation data allowed assignment of the gene controlling glycoprotein expression (M6P1) to chromosome 6. Similar analysis with translocation hybrids gave a regional assignment to 6q14-q15. M6P1 is distinct from NT5, coding for 5' nucleotidase, which maps to the same region.
    • TSLC1 gene silencing in cervical cancer cell lines and cervical neoplasia.

      Steenbergen, R D; Kramer, D; Braakhuis, B J; Stern, Peter L; Verheijen, René H; Meijer, C J; Snijders, P J; Department of Pathology, Unit of Molecular Pathology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands. r.steenbergen@vumc.nl (2004-02-18)
      BACKGROUND: Cervical carcinogenesis is initiated by infection with high-risk (i.e., carcinogenic) human papillomavirus (HPV) types. The subsequent progression from premalignant cervical intraepithelial neoplasia (CIN) to invasive cancer is driven by both genetic and epigenetic processes. We assessed the role of the gene encoding the adhesion molecule tumor suppressor in lung cancer 1 (TSLC1) in this progression. METHODS: We analyzed TSLC1 gene expression by real-time quantitative reverse transcription-polymerase chain reaction, promoter methylation by sodium bisulfite genomic DNA sequencing, and allelic loss by microsatellite analysis in primary keratinocytes, in four non-tumorigenic HPV-immortalized human keratinocyte cell lines, and in 11 human cervical cancer cell lines that were positive for a high-risk HPV DNA type and in normal cervical epithelial cells. We transfected cervical cancer SiHa cells that did not express TSLC1 mRNA with an expression vector containing the TSLC1 complementary DNA (cDNA) or an empty vector and analyzed transfectants for anchorage-independent growth and tumorigenicity in nude mice. We also examined TSLC1 promoter methylation in premalignant cervical lesions and in cervical carcinomas and smears. All statistical tests were two-sided. RESULTS: TSLC1 mRNA was strongly reduced, relative to levels in primary keratinocytes, or absent in 10 (91%) of 11 cervical carcinoma cell lines but in none (0%) of the four HPV-immortalized cell lines (difference = 91%, 95% confidence interval [CI] = 74% to 100%; P =.004). The TSLC1 promoter was hypermethylated, relative to normal foreskin and cervical epithelial cells, in nine (82%) of the 11 cervical carcinoma cell lines but in none (0%) of the four HPV-immortalized cell lines (difference = 82%, 95 CI = 59% to 100%; P =.01). Seven (88%, 95% CI = 47% to 100%) of the eight SiHa/TSLC1 transfectants displayed a marked reduction in anchorage-independent growth (i.e., 0-100 colonies per 5000 cells) compared with none of the four (0%, 95% CI = 0% to 60%) SiHa transfectants bearing the empty vector (i.e., SiHa/hygro transfectants; difference = 88%, 95% CI = 65% to 100%; P =.01) or untransfected SiHa cells. All seven mice (100%, 95% CI = 59% to 100%) injected with untransfected SiHa cells or SiHa/hygro transfectants displayed tumors of at least 50 mm(3) by 2-6 weeks after injection compared with none of eight mice (0%, 95% CI = 0% to 37%) injected with the SiHa/TSLC1 transfectants (difference = 100%, 95% CI = 68% to 100%; P<.001). We detected TSLC1 promoter hypermethylation in seven (35%, 95% CI = 15% to 59%) of 20 high-grade CIN lesions (i.e., CIN II and III) and in 30 (58%, 95% CI = 43% to 71%) of 52 cervical squamous cell carcinomas compared with none (0%, 95% CI = 0% to 34%) of nine normal cervical epithelial biopsy samples and none (0%, 95% CI = 0% to 22%) of 12 CIN I lesions (P<.001 for cervical squamous cell cancer versus normal epithelial biopsy samples plus CIN I lesions). CONCLUSIONS: TSLC1 gene silencing via promoter hypermethylation is a frequent event in the progression from high-risk HPV-containing, high-grade CIN lesions to invasive cervical cancer.
    • TTC5 is required to prevent apoptosis of acute myeloid leukemia stem cells.

      Lynch, J T; Somerville, Tim D D; Spencer, Gary J; Huang, Xu; Somervaille, Tim C P; Cancer Research UK Leukaemia Biology Laboratory, Paterson Institute for Cancer Research, The University of Manchester, Manchester, UK. (2013)
      Using a screening strategy, we identified the tetratricopeptide repeat (TPR) motif protein, Tetratricopeptide repeat domain 5 (TTC5, also known as stress responsive activator of p300 or Strap) as required for the survival of human acute myeloid leukemia (AML) cells. TTC5 is a stress-inducible transcription cofactor known to interact directly with the histone acetyltransferase EP300 to augment the TP53 response. Knockdown (KD) of TTC5 induced apoptosis of both murine and human AML cells, with concomitant loss of clonogenic and leukemia-initiating potential; KD of EP300 elicited a similar phenotype. Consistent with the physical interaction of TTC5 and EP300, the onset of apoptosis following KD of either gene was preceded by reduced expression of BCL2 and increased expression of pro-apoptotic genes. Forced expression of BCL2 blocked apoptosis and partially rescued the clonogenic potential of AML cells following TTC5 KD. KD of both genes also led to the accumulation of MYC, an acetylation target of EP300, and the form of MYC that accumulated exhibited relative hypoacetylation at K148 and K157, residues targeted by EP300. In view of the ability of excess cellular MYC to sensitize cells to apoptosis, our data suggest a model whereby TTC5 and EP300 cooperate to prevent excessive accumulation of MYC in AML cells and their sensitization to cell death. They further reveal a hitherto unappreciated role for TTC5 in leukemic hematopoiesis.
    • Tubulin as a target for anticancer drugs: agents which interact with the mitotic spindle.

      Jordan, Allan M; Hadfield, John A; Lawrence, N J; McGown, Alan T; Department of Chemistry, University of Manchester Institute of Science and Technology, UK. (1998-07)
      Tubulin is the biochemical target for several clinically used anticancer drugs, including paclitaxel and the vinca alkaloids vincristine and vinblastine. This review describes both the natural and synthetic agents which are known to interact with tubulin. Syntheses of the more complex agents are referenced and the potential clinical use of the compounds is discussed. This review describes the biochemistry of tubulin, microtubules, and the mitotic spindle. The agents are discussed in relation to the type of binding site on the protein with which they interact. These are the colchicine, vinca alkaloid, rhizoxin/maytansine, and tubulin sulfhydryl binding sites. Also included are the agents which either bind at other sites or unknown sites on tubulin. The literature is reviewed up to October 1997.
    • Tubulin-binding dibenz[c,e]oxepines as colchinol analogues for targeting tumour vasculature.

      Edwards, David J; Hadfield, John A; Wallace, T; Ducki, S; School of Chemistry, The University of Manchester, Oxford Road, Manchester, UK M13 9PL. (2011-01-07)
      Various methoxy- and hydroxy-substituted dibenz[c,e]oxepines were prepared via the copper(I)-induced coupling of ether-tethered arylstannanes or the dehydrative cyclisation of 1,1'-biphenyl-2,2'-dimethanols, assembled using the Ullmann cross-coupling of ortho-bromoaryl carbonyl compounds. The dibenzoxepines were screened for their ability to inhibit tubulin polymerisation and the in vitro growth of K562 human chronic myelogenous leukemia cells. The most active was 5,7-dihydro-3,9,10,11-tetramethoxydibenz[c,e]oxepin-4-ol, whose tubulin inhibitory and cytotoxicity (IC(50)) values were 1 μM and 40 nM, respectively.
    • Tumor apoptosis in cervical cancer: its role as a prognostic factor in 42 radiotherapy patients.

      Kim, Joo-Young; Cho, Hyun Yee; Lee, Kyu Chan; Hwang, You Jin; Lee, Myung Hak; Roberts, Stephen A; Kim, Chul-Hwan; Department of Radiation Oncology, Gil Medical Center, Gachon Medical College, Inchon, Korea. (2001-10-20)
      To investigate tumor apoptosis as a prognostic factor for outcome following radiation therapy, comparisons were made of apoptotic index (AI) as a predictor of short- vs. long-term response and pretreatment vs. radiation-induced apoptosis. Forty-two patients with proven squamous cell carcinoma of the uterine cervix were treated by radiation alone. Apoptosis was measured by light microscopic observation of hematoxylin and eosin-stained sections from biopsies taken before treatment and 4 and 24 hr after 2 Gy. Patients were evaluated at the end of the external radiation for determination of short-term response and for long-term outcome as well (median follow-up of 27 months). Patients with high spontaneous AI showed poor short-term response, local control, and survival. The significance of AI as a predictor of short-term response was lost after allowing for differences in tumor size. The positive predictive value of AI for local control and survival was independent of tumor size and stage. High AI was associated with poor local control and long-term prognosis in advanced squamous cell carcinoma of the cervix. The in vivo radiation-induced AI after 4 or 24 hr did not predict radiation therapy outcome.
    • Tumor cells induce the cancer associated fibroblast phenotype via caveolin-1 degradation: Implications for breast cancer and DCIS therapy with autophagy inhibitors.

      Martinez-Outschoorn, Ubaldo E; Pavlides, Stephanos; Whitaker-Menezes, Diana; Daumer, Kristin M; Milliman, Janet N; Chiavarina, Barbara; Migneco, Gemma; Witkiewicz, Agnieszka K; Martinez-Cantarin, Maria P; Flomenberg, Neal; et al. (2010-06-12)
      Loss of stromal caveolin 1 (Cav-1) is a novel biomarker for cancer-associated fibroblasts that predicts poor clinical outcome in breast cancer and DCIS patients. We hypothesized that epithelial cancer cells may have the ability to drive Cav-1 downregulation in adjacent normal fibroblasts, thereby promoting the cancer associated fibroblast phenotype. To test this hypothesis directly, here we developed a novel co-culture model employing (i) human breast cancer cells (MCF7), and (ii) immortalized fibroblasts (hTERT-BJ1), which are grown under defined experimental conditions. Importantly, we show that co-culture of immortalized human fibroblasts with MCF7 breast cancer cells leads to Cav-1 downregulation in fibroblasts. These results were also validated using primary cultures of normal human mammary fibroblasts co-cultured with MCF7 cells. In this system, we show that Cav-1 downregulation is mediated by autophagic/lysosomal degradation, as pre-treatment with lysosome-specific inhibitors rescues Cav-1 expression. Functionally, we demonstrate that fibroblasts co-cultured with MCF7 breast cancer cells acquire a cancer associated fibroblast phenotype, characterized by Cav-1 downregulation, increased expression of myofibroblast markers and extracellular matrix proteins, and constitutive activation of TGFbeta/Smad2 signaling. siRNA-mediated Cav-1 downregulation mimics several key changes that occur in co-cultured fibroblasts, clearly indicating that a loss of Cav-1 is a critical initiating factor, driving stromal fibroblast activation during tumorigenesis. As such, this co-culture system can now be used as an experimental model for generating "synthetic" cancer associated fibroblasts (CAFs). More specifically, these "synthetic" CAFs could be used for drug screening to identify novel therapeutics that selectively target the Cav-1-negative tumor micro-environment. Our findings also suggest that chloroquine, or other autophagy/lysosome inhibitors, may be useful as anti-cancer agents, to therapeutically restore the expression of stromal Cav-1 in cancer associated fibroblasts. We discuss this possibility, in light of the launch of a new clinical trial that uses chloroquine to treat DCIS patients: PINC (Preventing Invasive Breast Neoplasia with Cholorquine) [See http://clinicaltrials.gov/show/NCT01023477].
    • Tumor growth rate (TGR) to monitor growth/predict response to lanreotide autogel use before, during and after PRRT in advanced GEP-NETS: data from the PRELUDE study

      Bodei, L; Srirajaskanthan, R; Grana, CM; Baldari, S; Shah, T; Lamarca, Angela; Courbon, F; Scheidhauer, K; Baudin, E; Roussy, G; et al. (2020)
    • Tumor heterogeneity

      Pe'er, D.; Ogawa, S.; Elhanani, O.; Keren, L.; Oliver, T. G; Wedge, David C; Not available (2021)
      Tumor heterogeneity was traditionally considered in the genetic terms, but it has now been broadened into many more facets. These facets represent a challenge in our understanding of cancer etiology but also provide opportunity for us to understand prognosis and therapy response.
    • Tumor infiltrating regulatory T cells: tractable targets for immunotherapy.

      Khan, A R; Dovedi, Simon J; Wilkinson, R W; Pritchard, D I; Doctoral Training Centre for Targeted Therapeutics, School of Pharmacy, University of Nottingham, Nottingham, UK. (2010-10)
      Several studies have linked tumor-infiltration by regulatory T cells with poor patient outcome. Targeting the mechanisms by which regulatory T cells traffic to and persist in the tumor may circumvent tumor immune-escape by de-restricting T cell-mediated cytotoxicity. In this review, we describe the principle axes that govern regulatory T cell migration and the mechanisms that underpin their immunosuppressive activity in cancer. Inhibiting either the migration or function of regulatory T cells may enhance host-anti-cancer immune responses and as such are attractive and tractable targets for therapeutic intervention.
    • Tumor necrosis factor alpha is a critical component of interleukin 13-mediated protective T helper cell type 2 responses during helminth infection.

      Artis, David; Humphreys, Neil E; Bancroft, Allison J; Rothwell, Nancy J; Potten, Christopher S; Grencis, Richard K; Immunology Group, School of Biological Sciences, University of Manchester, Manchester M13 9PT, United Kingdom. mqbsszda@man.ac.uk (1999-10-04)
      In vivo manipulation of cytokine and/or cytokine receptor expression has previously shown that resistance to infection with the caecum-dwelling helminth Trichuris muris is dependent on interleukin (IL)-4 and IL-13 while susceptibility is associated with a T helper cell type 1 (Th1) cytokine response. Using gene-targeted mice deficient in tumor necrosis factor (TNF) receptor signaling and anti-TNF-alpha monoclonal antibody treatment, we have extended these studies to reveal a critical role for TNF-alpha in regulation of Th2 cytokine-mediated host protection. In vivo blockade of TNF-alpha in normally resistant mice, although not altering IL-4, IL-5, or IL-13 production in the draining lymph node, significantly delayed worm expulsion for the duration of treatment. IL-13-mediated worm expulsion in IL-4 knockout (KO) mice was also shown to be TNF-alpha dependent, and could be enhanced by administration of recombinant TNF-alpha. Furthermore, TNF receptor KO mice failed to expel T. muris, producing high levels of parasite-specific immunoglobulin G2a and the generation of a predominantly Th1 response, suggesting that the absence of TNF function from the onset of infection dramatically alters the phenotype of the response. These results provide the first demonstration of the role of TNF-alpha in regulating Th2 cytokine-mediated responses at mucosal sites, and have implications for the design of rational therapies against helminth infection and allergy.
    • Tumor O(6)-methylguanine-DNA methyltransferase inactivation by oral lomeguatrib.

      Watson, Amanda J; Sabharwal, Ami; Thorncroft, Mary R; McGown, Gail; Kerr, Richard; Bojanic, Stana; Soonawalla, Zahir; King, Alexandra; Miller, Andrea; Waller, Sue; et al. (2010-01-15)
      PURPOSE: A major mechanism of resistance to chlorethylnitrosureas and methylating agents involves the DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT). We sought to determine the dose of oral 6-(4-bromo-2-thienyl) methoxy purin-2-amine (lomeguatrib), a pseudosubstrate inactivator of MGMT, required to render active protein undetectable 12 hours after dosing in prostate, primary central nervous system (CNS), and colorectal cancer patients. EXPERIMENTAL DESIGN: Lomeguatrib was administered orally as a single dose (20-160 mg) approximately 12 hours before tumor resection. Dose escalation was projected to continue until grade 2 toxicity or until complete inactivation of tumor MGMT was encountered. Total MGMT protein levels were quantified by ELISA, and active protein levels were quantified by biochemical assay. MGMT promoter methylation was determined in glioblastoma DNA by methylation-specific PCR. RESULTS: Thirty-seven patients were dosed with lomeguatrib, and 32 informative tumor samples were obtained. Mean total MGMT level varied between tumor types: 554 +/- 404 fmol/mg protein (+/-SD) for prostate cancer, 87.4 +/- 40.3 fmol/mg protein for CNS tumors, and 244 +/- 181 fmol/mg protein for colorectal cancer. MGMT promoter hypermethylation did not correlate with total protein expression. Consistent total MGMT inactivation required 120 mg of lomeguatrib in prostate and colorectal cancers. Complete consistent inactivation in CNS tumors was observed only at the highest dose of lomeguatrib (160 mg). CONCLUSIONS: Total MGMT inactivation can be achieved in prostate, primary CNS, and colorectal cancers with a single administration of 120 or 160 mg lomeguatrib. The dose needed did not correlate with mean total MGMT protein concentrations. One hundred twenty to 160 mg/d of lomeguatrib should be administered to achieve total MGMT inactivation in future studies.