• A critical assessment of the intestinal proliferon hypothesis.

      Neal, J Valerie; Potten, Christopher S; Paterson Laboratories, Christie Hospital and Holt Radium Institute, Withington, Manchester M20 9BX, England (1981-07-07)
    • A critical review of the cytogenetic effects of styrene with an emphasis on human population monitoring: a synopsis.

      Scott, David; Preston, R J; Cancer Research Campaign Department of Cancer Genetics, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, Great Britain. (1994)
    • Cross-linking and sequence specific alkylation of DNA by aziridinyl quinones. 2. Structure requirements for sequence selectivity.

      Hargreaves, Robert H J; Mayalarp, Stephen P; Butler, John; McAdam, S R; O'Hare, C C; Hartley, John A; CRC Department of Biophysical Chemistry, Drug Development, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, U.K. (1997-01-31)
      The cytotoxicities and DNA sequence selectivity for guanine-N7 alkylation of 22 mono- and disubstituted 2,5-diaziridinyl-1,4-benzoquinones have been investigated. Several quinones produced patterns of alkylation following reduction with a selectivity for 5'-TGC-3' sequences. This sequence selectivity appeared to be dependent only on the presence of a hydrogen in position-6 of the quinone. A computer model, based on published crystallographic data, was used to explain this selectivity. The sequence selective quinones were generally more cytotoxic that the quinones which reacted randomly.
    • Cross-linking and sequence specific alkylation of DNA BY aziridinylquinones. 1. Quinone methides.

      Mayalarp, Stephen P; Hargreaves, Robert H J; Butler, John; O'Hare, C C; Hartley, John A; CRC Department of Biophysical Chemistry, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, UK. (1996-01-19)
      The cytotoxicities and DNA cross-linking abilities of 16 1,4-benzoquinones have been investigated. All of the alkylmonoaziridinyl-1,4-benzoquinones were able to interstrand crosslink DNA after reduction and were cytotoxic in vitro. Compounds lacking an aziridine group were unable to cross-link DNA and were less cytotoxic. The methyl analogues were shown to preferentially react at TGC sequences. From comparing the structural requirements for crosslinking and the cytotoxicities, a mechanism has been proposed wherein some hydroquinones can associate and react at TGC sequences in DNA. These hydroquinones can subsequently autoxidize to form a reactive quinone methide which reacts at the opposite strand to form a cross-link.
    • Cross-linking and sequence-specific alkylation of DNA by aziridinylquinones. 3. Effects of alkyl substituents.

      Hargreaves, Robert H J; O'Hare, C Caroline; Hartley, John A; Ross, David; Butler, John; CRC Section of Drug Development and Imaging, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester M20 9BX, U. K. (1999-06-17)
      The cytotoxicities and DNA cross-linking abilities of several alkyl-substituted diaziridinylquinones have been investigated. The cytotoxicities were determined in DT-diaphorase-rich (H460 and HT29) and -deficient (H596 and BE) cell lines. It was shown that the cytotoxicities in these cell lines correlated with the relative rates of reduction by the purified human enzyme and with the cross-linking efficiencies. The rates of reduction by DT-diaphorase were more dependent on the structures of the compounds than the reduction potentials, as determined by cyclic voltammetry. A computer model was also used to explain high efficiency of cross-linking and the GNC sequence selectivity of the reduced methyl-substituted diaziridinylquinones.
    • Cross-linking between histones and DNA following treatment with a series of dimethane sulphonate esters.

      Hartley, John A; Fox, Brian W; Paterson Laboratories, Christie Hospital and Holt Radium Institute, Wilmslow Road, Withington, Manchester M20 9BX, UK (1986)
      The cross-linking of the nucleohistone to the associated DNA by a series of methanesulphonates of the busulphan series (CH3SO2O(CH2)nOSO2CH3) from n = 4-9 has been studied by gel electrophoresis, by the use of 35S labelling and by pyrenemaleimide competition. It has been shown that all the dimethanesulphonates react with the Cys 114 of histone H3, and that octamethylene dimethanesulphonate (n = 8) cross-links histone H3 with DNA via the sulphydryl group, as well as forming H3-H3 dimers.
    • Cross-resistance studies on two K562 sublines resistant to diaziridinylbenzoquinones.

      Ward, Timothy H; Haran, M Sally; Whittaker, Dee; Watson, Amanda J; Howard, Tina D; Butler, John; CRC Department of Cell Culture, Paterson Institute for Cancer Research, Christie Hospital, Manchester, U.K. (1995-08-08)
      Two resistant K562 sublines have been developed by treatment with AZQ (2,5-bis(carboethoxyamino)-3,6-diaziridinyl-1,4-benzoquinone) and BZQ (2,5-bis(2-hydroxyethylamino)-3,6-diaziridinyl-1,4-benzoquinone). The ID50 values of for AZQ on K562, the AZQ-resistant sublines (AZQR) and the BZQ-resistant sublines (BZQR) were 0.063, 1.47 and 0.244 microM, respectively. The relative ID50 values for BZQ on the same cell lines were 0.2, 0.67 and 0.83 microM, respectively. Although it is generally believed that these two quinones function by different mechanisms, the two sublines have similar decreased levels of cytochrome P-450 reductase and DT-diaphorase and increased levels of glutathione and superoxide dismutase, compared to the parent cell line. The sublines are also cross-resistant to adriamycin, mitozolamide, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and mitomycin C. This work indicates the potential multifactorial mechanisms by which drug resistance can be induced in cell lines in the absence of conventional 'P'-glycoprotein multidrug resistance.
    • Crosstalk between chromatin structure, cohesin activity and transcription

      Maya-Miles, D; Andujar, E; Perez-Alegre, M; Murillo-Pineda, M; Barrientos-Moreno, M; Cabello-Lobato, Maria J; Gomez-Marin, E; Morillo-Huesca, M; Prado, F; Department of Genome Biology, Andalusian Molecular Biology and Regenerative Medicine (CABIMER), CSIC-University of Seville-University Pablo de Olavide, Seville, Spain (2019)
      BACKGROUND: A complex interplay between chromatin and topological machineries is critical for genome architecture and function. However, little is known about these reciprocal interactions, even for cohesin, despite its multiple roles in DNA metabolism. RESULTS: We have used genome-wide analyses to address how cohesins and chromatin structure impact each other in yeast. Cohesin inactivation in scc1-73 mutants during the S and G2 phases causes specific changes in chromatin structure that preferentially take place at promoters; these changes include a significant increase in the occupancy of the - 1 and + 1 nucleosomes. In addition, cohesins play a major role in transcription regulation that is associated with specific promoter chromatin architecture. In scc1-73 cells, downregulated genes are enriched in promoters with short or no nucleosome-free region (NFR) and a fragile nucleosome - 1/RSC complex" particle. These results, together with a preferential increase in the occupancy of nucleosome - 1 of these genes, suggest that cohesins promote transcription activation by helping RSC to form the NFR. In sharp contrast, the scc1-73 upregulated genes are enriched in promoters with an "open" chromatin structure and are mostly at cohesin-enriched regions, suggesting that a local accumulation of cohesins might help to inhibit transcription. On the other hand, a dramatic loss of chromatin integrity by histone depletion during DNA replication has a moderate effect on the accumulation and distribution of cohesin peaks along the genome. CONCLUSIONS: Our analyses of the interplay between chromatin integrity and cohesin activity suggest that cohesins play a major role in transcription regulation, which is associated with specific chromatin architecture and cohesin-mediated nucleosome alterations of the regulated promoters. In contrast, chromatin integrity plays only a minor role in the binding and distribution of cohesins."
    • Crosstalk between Notch, HIF-1α and GPER in breast cancer EMT.

      De Francesco, Ernestina M; Maggiolini, M; Musti, A; Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy. (2018-07-10)
      The Notch signaling pathway acts in both physiological and pathological conditions, including embryonic development and tumorigenesis. In cancer progression, diverse mechanisms are involved in Notch-mediated biological responses, including angiogenesis and epithelial-mesenchymal-transition (EMT). During EMT, the activation of cellular programs facilitated by transcriptional repressors results in epithelial cells losing their differentiated features, like cell⁻cell adhesion and apical⁻basal polarity, whereas they gain motility. As it concerns cancer epithelial cells, EMT may be consequent to the evolution of genetic/epigenetic instability, or triggered by factors that can act within the tumor microenvironment. Following a description of the Notch signaling pathway and its major regulatory nodes, we focus on studies that have given insights into the functional interaction between Notch signaling and either hypoxia or estrogen in breast cancer cells, with a particular focus on EMT. Furthermore, we describe the role of hypoxia signaling in breast cancer cells and discuss recent evidence regarding a functional interaction between HIF-1α and GPER in both breast cancer cells and cancer-associated fibroblasts (CAFs). On the basis of these studies, we propose that a functional network between HIF-1α, GPER and Notch may integrate tumor microenvironmental cues to induce robust EMT in cancer cells. Further investigations are required in order to better understand how hypoxia and estrogen signaling may converge on Notch-mediated EMT within the context of the stroma and tumor cells interaction. However, the data discussed here may anticipate the potential benefits of further pharmacological strategies targeting breast cancer progression.
    • Crypt base columnar cells in ileum of BDF1 male mice--their numbers and some features of their proliferation.

      Chwalinski, S; Potten, Christopher S; Department of Epithelial Biology, Christie Hospital and Holt Radium Institute, Manchester, England. (1989-12)
      Some features of the proliferative cells at the bottom of the ileal crypts in BDF1 mice have been studied in relation to the distribution of Paneth cells (PC) in an attempt to clarify the nature and function of these crypt base columnar cells (BCC) and to elucidate some aspects of the role of the microenvironment created by the PC. Longitudinal sections of crypts have shown that the ratio of PC to the BCC, which are scattered amongst the PC, is 2.7:1 in sections or approximately 29 PC and 9 BCC per whole crypt, i.e., a ratio of 3.2:1. The labelling index of BCC is about 35%, which is comparable to that of mid-crypt columnar cells. Although the BCC do become labeled, it is concluded that they cannot create vertical pairs or runs of several adjacent BCC since this would seriously disturb the distribution of Paneth cells. Only in dividing crypts are such runs (consisting of 3 to 5 cells) observed. The ability of BCC to synthesize DNA is not dependent on their position in the Paneth cell zone. In 95% of the crypts, the highest Paneth cell is below the 7th cell position from the bottom of the crypt, and the positions of the highest PC on either side of a given crypt are similar. The secreted granules or the cytoplasm of PC specifically bind pokeweed lectin, and this can be used for identification. Tracer doses of 3HTdR (37 kBq/gm body weight) result in the histological death of some BCC, and these damaged cells are evenly distributed throughout the Paneth cell zone. These tracer doses are somewhat selectively incorporated into BCC, i.e., the BCC have a higher grain count in autoradiographs, probably because they possess more thymidine kinase enzyme activity. This ability is very sensitive to the withdrawal of food, because 24 hr of fasting abolished the observed gradient in the intensity of labelling, which is very well correlated with the distribution of BCC. Regeneration of the crypts following cytotoxic exposure to Ara-C is initiated at the base of the crypt and hence may involve the BCC with possible help from the Paneth cells. The latter are insensitive to cytotoxic (S phase specific) agents and may help in the regeneration by preserving the architecture of the base of the crypt.
    • The crypt cycle in mouse small intestinal epithelium.

      Li, Y Q; Roberts, Stephen A; Paulus, U; Loeffler, M; Potten, Christopher S; CRC Department of Epithelial Biology, Paterson Institute for Cancer Research, Christie Hospital (NHS) Trust, Manchester, UK. (1994-12)
      We have used a mutation-induced marker system in the intestine of mice heterozygous at the Dlb-1 locus, which determines the expression of binding sites for the lectin Dolichos biflorus agglutinin, and the frequency of clustering of mutated crypts with time as a means of investigating the frequency of the crypt fission process and the crypt cycle. Whole-mount preparations from heterozygous Dlb-1b/Dlb-1a mice were stained with a peroxidase conjugate of Dolichos biflorus agglutinin. Mutations at the Dlb-1b locus in crypt stem cells result in loss of DBA-Px binding in these cells and subsequently their progeny, which eventually results in a rare isolated single, unstained crypt. The subsequent development of pairs, triplets and clusters of negative staining crypts has been assumed to be the result of crypt fission. The frequency of these fission events has been measured in control untreated mice. These negative crypts are the result of spontaneous mutations. We have also looked at mutated crypts after treatment with N-nitroso-N-ethylurea or N-methyl-N'-nitro-N-nitrosoguanidine of young adult mice, which elevates the number of mutations. Our results suggest that the crypt cycle in control animals is very long, 187 +/- 44 weeks (3.6 years, i.e. essentially the life of a laboratory mouse). This implies that about a third of the crypts may divide once in the life of a mouse. After sufficient time for conversion of mixed crypts to monophenotypic crypts after mutagen treatment several clusters of negative crypts were seen.(ABSTRACT TRUNCATED AT 250 WORDS)
    • Cryptogenic cells and proliferative cells in intestinal epithelium.

      Hendry, Jolyon H; Potten, Christopher S; Paterson Laboratories, CHristie Hospital and Holt Radium Institute, Manchester (1974-06)
    • CUL2(LRR1) , TRAIP and p97 control CMG helicase disassembly in the mammalian cell cycle

      Villa, F.; Fujisawa, R.; Ainsworth, J.; Nishimura, K.; Lie-A-Ling, Michael; Lacaud, Georges; Labib, K. P.; The MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee (2021)
      The eukaryotic replisome is disassembled in each cell cycle, dependent upon ubiquitylation of the CMG helicase. Studies of Saccharomyces cerevisiae, Caenorhabditis elegans and Xenopus laevis have revealed surprising evolutionary diversity in the ubiquitin ligases that control CMG ubiquitylation, but regulated disassembly of the mammalian replisome has yet to be explored. Here, we describe a model system for studying the ubiquitylation and chromatin extraction of the mammalian CMG replisome, based on mouse embryonic stem cells. We show that the ubiquitin ligase CUL2LRR1 is required for ubiquitylation of the CMG-MCM7 subunit during S-phase, leading to disassembly by the p97 ATPase. Moreover, a second pathway of CMG disassembly is activated during mitosis, dependent upon the TRAIP ubiquitin ligase that is mutated in primordial dwarfism and mis-regulated in various cancers. These findings indicate that replisome disassembly in diverse metazoa is regulated by a conserved pair of ubiquitin ligases, distinct from those present in other eukaryotes.
    • Cultured human T-cell lines kill autologous solid tumours.

      Vose, Brent M; Moore, Michael; Department of Immunology, Paterson Laboratories, Christie Hospital and Holt Radium Institute, Manchester M20 9BX (U.K.) (1981-10)
      Lymphocytes from peripheral blood, lymph node, spleen and tumour of 7 patients with various carcinomas (2 lung, 3 colon, 1 gastric and 1 parotid tumour) were cultured for 15 days in conditioned media containing T-cell growth factor (TCGF; Interleukin 2) after which their cytotoxic activity against autologous tumour (and in some instances, autologous normal) cells and allogeneic tumour targets was evaluated in a short-term 51Cr-release assay. Significant cytotoxicity against autologous tumour targets was detected in at least one effector preparation from all of the patients, under conditions where, in some cases, other autologous cells (normal lung, PHA-transformed lymphocytes) were resistant. This cytotoxicity also generally extended to allogeneic tumour targets, but lysis of K562, a cell line sensitive to natural killing, occurred in only 3 of 19 effector cell preparations. The data are consistent with a polyclonal expansion of cytotoxic T-cells of tumour-bearing patients which includes the amplification of a population recognitive of antigens expressed on autologous neoplastic cells.
    • Culturing primitive hemopoietic cells. Long-term mouse marrow cultures and the establishment of factor-dependent (FDCP-Mix) hemopoietic cell lines.

      Spooncer, Elaine; Dexter, T Michael; Department of Experimental Hematology, Paterson Laboratories, Christie Hospital, Manchester, UK. (1997)
    • Curative-intent metastasis-directed therapies for molecularly-defined oligorecurrent prostate cancer: a prospective phase ii trial testing the oligometastasis hypothesis

      Glicksman, R. M.; Metser, U.; Vines, D.; Valliant, J.; Liu, Z.; Chung, P. W.; Bristow, Robert G; Finelli, A.; Hamilton, R.; Fleshner, N. E.; et al. (2021)
      Background: The hypothesis of a curable oligometastatic prostate cancer (PCa) state remains to be clinically-proven. Conventional imaging often fails to localize early recurrences, hampering the potential for radical approaches. Objective: We hypothesize that prostate-specific membrane antigen (PSMA)-targeted PET-MR/CT allows for earlier detection and localization of oligorecurrent-PCa, unveiling a molecularly-defined state amenable to curative-intent metastasis-directed treatment (MDT). Design/setting/participants: Single-institution single-arm phase-two study. Patients with rising PSA (0.4-3.0 ng/mL) after maximal local therapy (radical prostatectomy and post-operative radiotherapy), negative conventional staging, and no prior salvage hormonal therapy (HT) were eligible. Interventions: All patients underwent [18F]DCFPyL PET-MR/CT. Patients with molecularly-defined oligorecurrent-PCa had MDT (stereotactic ablative body radiotherapy [SABR] or surgery) without HT. Outcome measurements/statistical analysis: Primary endpoint was biochemical response (complete, i.e. biochemical 'no evidence of disease' [bNED], or partial response [100% or ≥50% PSA decline from baseline, respectively]) after MDT. Simon's two-stage design was employed (null and alternate hypotheses <5% and >20% response rate, respectively), with α and β of 0.1. Results: Seventy-two patients were enrolled (May/2017-July/2019). Thirty-eight (53%) had PSMA-detected oligorecurrent-PCa amenable for MDT. Thirty-seven (51%) agreed to MDT: 10 and 27 underwent surgery and SABR, respectively. Median follow-up was 15.9 months (IQR 9.8-19.1). Of patients receiving MDT, the overall response rate was 60%, including 22% rendered bNED. One (2.7%) grade 3 toxicity (intra-operative ureteric injury) was observed. Conclusions: PSMA-defined oligorecurrent-PCa can be rendered bNED, a necessary step towards cure, in 1 of 5 patients receiving MDT alone. Randomized trials are justified to determine if MDT +/- systemic agents can expand the curative therapeutic armamentarium for PCa. Patient summary: We studied men treated for prostate cancer with rising PSA. We found PSMA imaging detected recurrent cancer in three-quarters of patients, and targeted treatment to these areas significantly decreased PSA in half of patients.
    • Current models, challenges and best practices for work conducted between European academic cooperative groups and industry

      Stahel, RA; Lacombe, D; Cardoso, F; Casali, PG; Negrouk, A; Marais, Richard; Hiltbrunner, A; Vyas, M; Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland (2020)
    • Current results with rhizoxin: the evaluation of a clinical and a basic scientist.

      Fox, Brian W; Paterson Institute for Cancer Research, Christie Hospital & Holt Radium Institute, Manchester, U.K. (1992-11)
    • Current status of tumor markers in large bowel cancer.

      Moore, Michael; Jones, David J; Schofield, Philip F; Harnden, David G (1989)
      The aim of a primary screening system is to detect premalignant lesions and carcinomas when amenable to "curative" surgery. Although a number of "classical" tumor markers have acquired potential for clinical management, none is presently adequate for presymptomatic diagnosis or screening. In colorectal carcinoma, the screening potential of carcinoembryonic antigen (CEA), the gastrointestinal-related antigen, CA19-9, and other more recently characterized "biochemical markers" is virtually nonexistent, even in patients at high risk to develop the disease. Promising new leads are beginning to emerge from somatic cell genetic and molecular biological approaches. In common with other epithelial neoplasms, perturbations in oncogene expression have been demonstrated in colorectal cancers, and probably reflect important events in malignant transformation and progression. Studies of oncogene expression have, however, not yet yielded clinically useful information. Recently, an intensive search for specific chromosomal and gene abnormalities in the hereditary colon cancer syndromes led to the location of the familial adenomatous polyposis (FAP) gene at chromosome 5q21-q22. Significant is that the loss of alleles on chromosome 5 has also been observed in the tumor cells of at least 20% of sporadic colon cancer patients. This type of association between constitutional genetic change and genetic aberration in the cells of sporadic tumors is reminiscent of other malignant diseases with a genetic component (e.g., retinoblastoma and Wilms' tumor).(ABSTRACT TRUNCATED AT 250 WORDS)
    • Curvature delays growth-induced wrinkling

      Jia, F; Pearce, Simon P; Goriely, A; School of Manufacturing Science and Engineering, Southwest University of Science and Technology, Sichuan 621010, China (2018)
      Wrinkling patterns can be induced by the growth of a thin elastic film over a soft elastic substrate. While there is a good understanding of how this pattern is initiated on a flat geometry, wrinkling patterns over a curved surface are more complicated. Here, we consider this phenomenon within the framework of large deformation morphoelasticity by investigating surface wrinkling of a growing thin elastic film bonded to a large elastic cylinder. The system has two important dimensionless parameters: the ratio ? of the film thickness by the cylinder radius and the relative stiffness of the two layers ?. Depending on the values of ? and ? we identify four different regimes for which we find the critical growth and wrinkling mode number. By combining asymptotic methods with numerical computations we determine the effect of the curvature on the bifurcation and establish that it always induces a delay at the bifurcation: Larger growth is needed on a curved surface to induce the same wrinkling instability. These results are crucial to understand pattern formation on surface with varying curvatures.