42 results on '"Linda J. Nicholson"'
Search Results
2. Allison Weir, Identities and Freedom: Feminist Theory Between Power and Connection
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Linda J. Nicholson
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Power (social and political) ,Feminist theory ,Philosophy ,Weir ,Gender studies ,General Medicine ,Epistemology ,Connection (mathematics) - Published
- 2014
3. Epigenetic downregulation of human disabled homolog 2 switches TGF-beta from a tumor suppressor to a tumor promoter
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Max Patridge, Karin A. Oien, Reshma Shah, Nelofer Syed, Darren I. O'Brien, Louise Hiller, Clare Orange, Blanca Herrera, Paul Smith, Martino Monteverde, Milena Gasco, Francesca M. Buffa, Jelena Mann, Cristiana Lo Nigro, Meghan E. Maurer, Laura Lattanzio, Jonathan A. Cooper, Adrian L. Harris, Margaret C. Frame, Gabriela Kalna, Tim Crook, Linda J. Nicholson, Adele Hannigan, Lindsay C. Spender, David C. K. Chu, Catharine M L West, Johanna K. Thurlow, and Gareth J. Inman
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Down-Regulation ,Smad2 Protein ,medicine.disease_cause ,Epigenesis, Genetic ,RC0254 ,Mice ,Downregulation and upregulation ,RNA interference ,Cell Movement ,Transforming Growth Factor beta ,Cell Line, Tumor ,medicine ,Gene silencing ,Animals ,Humans ,Smad3 Protein ,Promoter Regions, Genetic ,Adaptor Proteins, Signal Transducing ,Medicine(all) ,biology ,Cell growth ,Tumor Suppressor Proteins ,General Medicine ,Transforming growth factor beta ,DNA Methylation ,Head and Neck Neoplasms ,Cancer cell ,DNA methylation ,Immunology ,Cancer research ,biology.protein ,Carcinoma, Squamous Cell ,CpG Islands ,Carcinogenesis ,Apoptosis Regulatory Proteins ,Research Article - Abstract
The cytokine TGF-beta acts as a tumor suppressor in normal epithelial cells and during the early stages of tumorigenesis. During malignant progression, cancer cells can switch their response to TGF-beta and use this cytokine as a potent oncogenic factor; however, the mechanistic basis for this is poorly understood. Here we demonstrate that downregulation of disabled homolog 2 (DAB2) gene expression via promoter methylation frequently occurs in human squamous cell carcinomas (SCCs) and acts as an independent predictor of metastasis and poor prognosis. Retrospective microarray analysis in an independent data set indicated that low levels of DAB2 and high levels of TGFB2 expression correlate with poor prognosis. Immunohistochemistry, reexpression, genetic knockout, and RNAi silencing studies demonstrated that downregulation of DAB2 expression modulated the TGF-beta/Smad pathway. Simultaneously, DAB2 down-regulation abrogated TGF-beta tumor suppressor function, while enabling TGF-beta tumor-promoting activities. Downregulation of DAB2 blocked TGF-beta-mediated inhibition of cell proliferation and migration and enabled TGF-beta to promote cell motility, anchorage-independent growth, and tumor growth in vivo. Our data indicate that DAB2 acts as a tumor suppressor by dictating tumor cell TGF-beta responses, identify a biomarker for SCC progression, and suggest a means to stratify patients with advanced SCC who may benefit clinically from anti-TGF-beta therapies.
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- 2016
4. Cancer stem cells: problems for therapy?
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Linda J. Nicholson, Lim Sm, and Malcolm R. Alison
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Epithelial-Mesenchymal Transition ,Notch signaling pathway ,Biology ,Pathology and Forensic Medicine ,Cell therapy ,Mice ,Cancer stem cell ,Neoplasms ,microRNA ,medicine ,Animals ,Humans ,Neoplasm Invasiveness ,Epithelial–mesenchymal transition ,Neoplasm Metastasis ,Wnt signaling pathway ,Cancer ,Neoplasms, Experimental ,Prognosis ,medicine.disease ,Cell Transformation, Neoplastic ,Immunology ,Disease Progression ,Neoplastic Stem Cells ,Cancer research ,Stem cell - Abstract
Many, if not all, tumours contain a sub-population of self-renewing and expanding stem cells known as cancer stem cells (CSCs). The symmetric division of CSCs is one mechanism enabling expansion in their numbers as tumours grow, while epithelial-mesenchymal transition (EMT) is an increasingly recognized mechanism to generate further CSCs endowed with a more invasive and metastatic phenotype. Putative CSCs are prospectively isolated using methods based on either a surface marker or an intracellular enzyme activity and then assessed by a 'sphere-forming' assay in non-adherent culture and/or by their ability to initiate new tumour growth when xenotransplanted into immunocompromised mice-hence, these cells are often referred to as tumour-propagating cells (TPCs). Cell sub-populations enriched for tumour-initiating ability have also been found in murine tumours, countering the argument that xenografting human cells merely select human cells with an ability to grow in mice. Cancer progression can be viewed as an evolutionary process that generates new/multiple clones with a fresh identity; this may be a major obstacle to successful cancer stem cell eradication if treatment targets only a single type of stem cell. In this review, we first briefly discuss evidence that cancer can originate from normal stem cells or closely related descendants. We then outline the attributes of CSCs and review studies in which they have been identified in various cancers. Finally, we discuss the implications of these findings for successful cancer therapies, concentrating on the self-renewal pathways (Wnt, Notch, and Hedgehog), aldehyde dehydrogenase activity, EMT, miRNAs, and other epigenetic modifiers as potential targets for therapeutic manipulation.
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- 2010
5. Finding cancer stem cells: are aldehyde dehydrogenases fit for purpose?
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Naomi Guppy, Linda J. Nicholson, Lim Sm, and Malcolm R. Alison
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Male ,Aldehyde dehydrogenase ,Stem cell marker ,Pathology and Forensic Medicine ,Mice ,Breast cancer ,Cancer stem cell ,Neoplasms ,Biomarkers, Tumor ,medicine ,Animals ,Humans ,biology ,Stem Cells ,Aldehyde Dehydrogenase ,Cell sorting ,Prognosis ,medicine.disease ,Biochemistry ,Neoplastic Stem Cells ,biology.protein ,Cancer research ,Female ,Stem cell ,Antibody ,Multipotentiality - Abstract
Despite many years of intensive effort, there is surprisingly little consensus on the most suitable markers with which to locate and isolate stem cells from adult tissues. By comparison, the study of cancer stem cells is still in its infancy; so, unsurprisingly, there is great uncertainty as to the identity of these cells. Stem cell markers can be broadly categorized into molecular determinants of self-renewal, clonogenicity, multipotentiality, adherence to the niche, and longevity. This review assesses the utility of recognizing cancer stem cells by virtue of high expression of aldehyde dehydrogenases (ALDHs), probably significant determinants of cell survival through their ability to detoxify many potentially cytotoxic molecules, and contributing to drug resistance. Antibodies are available against the ALDH enzyme family, but the vast majority of studies have used cell sorting techniques to enrich for cells expressing these enzymes. Live cells expressing high ALDH activity are usually identified by the ALDEFLUOR kit and sorted by fluorescence activated cell sorting (FACS). For many human tumours, but notably breast cancer, cell selection based upon ALDH activity appears to be a useful marker for enriching for cells with tumour-initiating activity (presumed cancer stem cells) in immunodeficient mice, and indeed the frequency of so-called ALDH(bri) cells in many tumours can be an independent prognostic indicator.
- Published
- 2010
6. Epigenetic silencing of argininosuccinate synthetase confers resistance to platinum-induced cell death but collateral sensitivity to arginine auxotrophy in ovarian cancer
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Tim Crook, Christopher Kimberley, Dominique Koensgen, Louise Hiller, Peter Schmid, Linda J. Nicholson, Alexander Mustea, Paul R. Smith, Peter W. Szlosarek, and Jalid Sehouli
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Cancer Research ,medicine.medical_specialty ,Paclitaxel ,endocrine system diseases ,Arginine ,Immunoblotting ,Argininosuccinate synthase ,Argininosuccinate Synthase ,Carboplatin ,chemistry.chemical_compound ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Tumor Cells, Cultured ,medicine ,Humans ,Gene Silencing ,Epigenetics ,Promoter Regions, Genetic ,Ovarian Neoplasms ,Cisplatin ,Cell Death ,biology ,Cancer ,DNA Methylation ,Middle Aged ,medicine.disease ,female genital diseases and pregnancy complications ,Cystadenocarcinoma, Serous ,Gene Expression Regulation, Neoplastic ,Survival Rate ,Endocrinology ,Oncology ,chemistry ,Drug Resistance, Neoplasm ,DNA methylation ,biology.protein ,Cancer research ,Female ,Ovarian cancer ,medicine.drug - Abstract
Evidence indicates that acquired resistance of cancers to chemotherapeutic agents can occur via epigenetic mechanisms. Down-regulation of expression of argininosuccinate synthetase (ASS1), the rate-limiting enzyme in the biosynthesis of arginine, has been associated with the development of platinum resistance in ovarian cancer treated with platinum-based chemotherapy. The aim of the present study was to analyse epigenetic regulation of ASS1 in ovarian cancer tissue taken at diagnosis and relapse and determine its significance as a predictor of clinical outcome in patients treated with platinum-based chemotherapy. In addition, expression and epigenetic regulation of ASS1 were analysed in human ovarian cancer cell lines, and ASS1 expression correlated with the ability of the lines to grow in media containing cisplatin, carboplatin or taxol or in arginine-depleted media. Our results show that aberrant methylation in the ASS1 promoter correlated with transcriptional silencing in ovarian cancer cell lines. ASS1 silencing conferred selective resistance to platinum-based drugs and conferred arginine auxotrophy and sensitivity to arginine deprivation. In ovarian cancer, ASS1 methylation at diagnosis was associated with significantly reduced overall survival (p = 0.01) and relapse-free survival (p = 0.01). In patients who relapse, ASS1 methylation was significantly more frequent at relapse (p = 0.008). These data establish epigenetic inactivation of ASS1 as a determinant of response to platinum chemotherapy and imply that transcriptional silencing of ASS1 contributes to treatment failure and clinical relapse in ovarian cancer. The collateral sensitivity of cells lacking endogenous ASS1 to arginine depletion suggests novel therapeutic strategies for the management of relapsed ovarian cancer.
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- 2009
7. Ras-MEK-ERK signaling cascade regulates androgen receptor element-inducible gene transcription and DNA synthesis in prostate cancer cells
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Rashida Pramanik, Gordon Muir, Anne Marie Carey, Jonathan D.H. Morris, Linda J. Nicholson, Francis Martin, and Tracy Dew
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Male ,MAPK/ERK pathway ,Cancer Research ,Neoplasms, Hormone-Dependent ,Transcription, Genetic ,Biology ,urologic and male genital diseases ,Methionine ,DU145 ,Genes, Reporter ,Nitriles ,LNCaP ,Butadienes ,Tumor Cells, Cultured ,Humans ,Extracellular Signal-Regulated MAP Kinases ,Cell Proliferation ,Mitogen-Activated Protein Kinase Kinases ,Regulation of gene expression ,Reporter gene ,DNA synthesis ,Prostatic Neoplasms ,DNA, Neoplasm ,Gene Expression Regulation, Neoplastic ,Androgen receptor ,Oncology ,Receptors, Androgen ,ras Proteins ,Cancer research ,Signal transduction ,Signal Transduction - Abstract
Treatment of prostate cancer (CaP) patients frequently involves androgen ablation, but resistance often develops and androgen-insensitive tumors emerge. The molecular basis for the development of refractory CaP that grows in an androgen-independent manner is poorly understood, but alterations in growth factor signaling pathways are likely to be involved. We examined the growth factor modulation of androgen-receptor element (ARE)-inducible luciferase reporter gene activity and consequent DNA synthesis as a measure of proliferative growth in androgen-dependent LNCaP or androgen-independent PC3 or DU145 CaP cells. The synthetic androgen R1881 stimulated ARE-inducible reporter gene activity and prostate-specific antigen expression in LNCaP cells and the MEK/ERK inhibitor U0126 or the anti-androgen bicalutamide (casodex) prevented both of these responses. Activated V12-Ha-Ras expression in LNCaP cells also stimulated ARE-inducible gene transcription, and U0126 or the farnesyltransferase inhibitor FTI-277 but not bicalutamide blocked this. ARE-inducible reporter gene activity was elevated already in PC3 cells, and ERK was constitutively activated in serum-starved LNCaP or DU145 cells. U0126 inhibited each of these responses and also inhibited DNA synthesis in all 3 CaP cell lines. These results demonstrate that chronic stimulation of the Ras-MEK-ERK signaling pathway can sustain ARE-inducible gene transcription and growth of CaP cells, and suggests that components of this pathway may offer targets for cancer therapy.
- Published
- 2007
8. A new role for the anti-apoptotic gene A20 in angiogenesis
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Richard Camplejohn, Linda J. Nicholson, Ian R. Hart, Michael G. Stone, and Hsiao W. Chng
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Umbilical Veins ,Angiogenesis ,Down-Regulation ,Neovascularization, Physiologic ,Apoptosis ,Biology ,Transfection ,Umbilical vein ,Neovascularization ,Downregulation and upregulation ,immune system diseases ,hemic and lymphatic diseases ,medicine ,Humans ,RNA, Small Interfering ,Cells, Cultured ,Tumor Necrosis Factor alpha-Induced Protein 3 ,Matrigel ,Intracellular Signaling Peptides and Proteins ,Endothelial Cells ,Nuclear Proteins ,Proteins ,Cell Biology ,Coculture Techniques ,DNA-Binding Proteins ,Transplantation ,Tubule ,Immunology ,Cancer research ,Tumor Suppressor Protein p53 ,medicine.symptom - Abstract
A20 is a negative regulator of NF-kappaB activation and thus a potential therapeutic tool for the treatment of diseases where apoptosis and/or inflammatory responses are part of the pathogenic process. Thus, A20 has been shown to improve the long-term outcome of organ transplantation, particularly, the transplantation of islets of Langerhans which may aid the cure of type I diabetes. We now report a new role for A20 in regulating neovascularisation. We used RNA interference to inhibit A20 expression in primary human umbilical vein endothelial cells (HUVECs) and investigated the effect on tubule formation in two in vitro angiogenesis assays, Matrigel and a co-culture assay. Tubule area and tubule length were both reduced following inhibition of A20 expression in HUVECs. These inhibitory effects were particularly evident in the co-culture assay, which incorporates the critical steps of the angiogenic process and ultimately results in the formation of an intricate network of anastomosing tubules that resemble the formed capillary bed: a partial down-regulation of A20 protein (50-60%) resulted in a 28% reduction in tubule area (P < 0.05) and a 26% reduction in tubule length (P < 0.05). A20 may offer a new target in the treatment of human conditions, including cancer, which are characterised by neovascularisation.
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- 2006
9. A Response to My 'Critics'
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Linda J. Nicholson
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Gender Studies ,Philosophy - Published
- 2001
10. A20 RNA expression is associated with undifferentiated nasopharyngeal carcinoma and poorly differentiated head and neck squamous cell carcinoma
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Jonathan R. Salisbury, Linda J. Nicholson, Graham Packham, and J. D. Codd
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Pathology ,medicine.medical_specialty ,Biology ,medicine.disease_cause ,medicine.disease ,Epstein–Barr virus ,Head and neck squamous-cell carcinoma ,Pathology and Forensic Medicine ,Gene product ,stomatognathic diseases ,Nasopharyngeal carcinoma ,Epidermoid carcinoma ,immune system diseases ,hemic and lymphatic diseases ,Gene expression ,otorhinolaryngologic diseases ,medicine ,Carcinoma ,Lymphoepithelioma - Abstract
A20 is an anti-apoptotic gene that can be induced in human epithelial cell lines in response to expression of the Epstein–Barr virus (EBV) gene product latent membrane protein 1 (LMP1). EBV is a ubiquitous, persistent human herpesvirus that is consistently associated with undifferentiated nasopharyngeal carcinoma (NPC), in which antigen expression includes LMP1. Consistent with a potential role in the development of NPC, LMP1 has profound effects on epithelial cell growth. A20 may be a key downstream effector of LMP1 in NPC, as LMP1-induced A20 blocks p53-mediated apoptosis in H1299 epithelial cells and most NPCs have wild-type p53. Moreover, the potential role of A20 in the development of epithelial malignancies may extend to tumours not associated with EBV. The purpose of this study was to develop an in situ hybridization assay to assess expression of A20 RNA in undifferentiated NPC and in non-EBV-associated poorly differentiated head and neck squamous cell carcinomas (SCCs) and well-differentiated SCCs of the skin. A20 RNA expression was also examined in normal samples of oral mucosa and skin. Expression of A20 was demonstrated in 76 per cent of undifferentiated NPCs and in 80 per cent of poorly differentiated head and neck SCCs, suggesting a role for A20 in the pathogenesis of these epithelial malignancies. By contrast, A20 RNA was not detected in well-differentiated SCCs of the skin, or in any normal samples of squamous epithelial tissue. The pathway leading to A20 expression in non-EBV-associated poorly differentiated head and neck SCCs is clearly LMP1-independent. LMP1 expression was demonstrated in 29 per cent of NPC biopsies, suggesting an LMP1-independent pathway to A20 induction in undifferentiated NPC. Copyright © 1999 John Wiley & Sons, Ltd.
- Published
- 1999
11. Epstein-Barr virus latent membrane protein does not inhibit differentiation and induces tumorigenicity of human epithelial cells
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I Johannessen, Linda J. Nicholson, David A. Thorley-Lawson, J. D. Codd, Jonathan R. Salisbury, Dorothy H Crawford, and P Hopwood
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Herpesvirus 4, Human ,Cancer Research ,endocrine system diseases ,Cell Transplantation ,viruses ,Cellular differentiation ,Transplantation, Heterologous ,Cell ,Mice, SCID ,Biology ,Transfection ,medicine.disease_cause ,Epithelium ,Cell Line ,Viral Matrix Proteins ,Mice ,hemic and lymphatic diseases ,otorhinolaryngologic diseases ,Genetics ,medicine ,Animals ,Humans ,Molecular Biology ,Epithelial cell differentiation ,Cell Differentiation ,Oncogene Proteins, Viral ,Cell Transformation, Viral ,medicine.disease ,Epstein–Barr virus ,Virology ,Recombinant Proteins ,stomatognathic diseases ,HaCaT ,Cell Transformation, Neoplastic ,medicine.anatomical_structure ,Nasopharyngeal carcinoma ,Cell culture ,Carcinoma, Squamous Cell ,Cancer research - Abstract
Latent membrane protein (LMP) is a latent Epstein-Barr virus (EBV) protein expressed in the EBV associated malignancy, nasopharyngeal carcinoma (NPC). Properties ascribed to this protein include inhibition of epithelial cell differentiation and deregulation of epithelial cellular gene expression, and are believed to contribute to the development of NPC. Studies to evaluate the oncogenic potential of LMP in epithelial cells have not been conclusive. We carried out studies to determine the tumorigenic activity of LMP in two human epithelial cell lines, SCC12F and HaCaT; while SCC12F LMP transfectants were non-tumorigenic in severe combined immunodeficient mice, HaCaT LMP transfectants were strongly oncogenic. The tumours produced were well differentiated, keratinising squamous cell carcinomas suggesting that LMP does not inhibit epithelial cell differentiation which conflicts with a previous report by Dawson et al. (1990). To resolve this discrepancy we examined the ability of HaCaT and SCC12F LMP transfectants to differentiate in a suspension culture assay. Both lines were able to differentiate to a similar extent as parental lines and control transfectants. Our results indicate that LMP is strongly oncogenic in human epithelial cells but that inhibition of differentiation is not necessarily a mechanism by which LMP contributes to the pathogenesis of NPC.
- Published
- 1997
12. Seamless replacement of Autographa californica multiple nucleopolyhedrovirus gp64 with each of five novel type II alphabaculovirus fusion sequences generates pseudotyped virus that fails to transduce mammalian cells
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Marcel, Westenberg, Helen M, Soedling, Nisha, Hirani, Linda J, Nicholson, Derek A, Mann, and Colin T, Dolphin
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Mammals ,Recombination, Genetic ,Insecta ,Animal ,viruses ,fungi ,Host Specificity ,Standard ,Cell Line ,Lepidoptera ,Viral Proteins ,Transformation, Genetic ,DNA, Viral ,Animals ,Humans ,DNA viruses ,Baculoviridae - Abstract
Autographa californica multiple nucleopolyhedrovirus (AcMNPV), a member of the type I alphabaculoviruses, is able to transduce and deliver a functional gene to a range of non-host cells, including many mammalian lines and primary cells, a property mediated by the envelope fusion protein GP64. AcMNPV is non-cytopathic and inherently replication deficient in non-host cells. As such, AcMNPV represents a possible new class of gene therapy vector with potential future clinical utility. Whilst not a problem for in vitro gene delivery, the broad tropism displayed for non-host cells is less desirable in a gene therapy vector. The fusion protein F of type II alphabaculoviruses can substitute functionally for GP64, and such pseudotyped viruses display a severely impaired capacity for non-host-cell transduction. Thus, surface decoration of such an F-pseudotyped AcMNPV with cell-binding ligands may restore transduction competence and generate vectors with desirable cell-targeting characteristics. By seamlessly swapping the native gp64 coding sequence with each of five sequences encoding different F proteins, a set of F-pseudotyped AcMNPV was generated. This report details their relative abilities both to functionally replace GP64 in viral growth and to transduce human Saos-2 and HeLa cells. All five supported viable infections in insect cell cultures and one, the Mamestra configurata NPV (MacoNPV) F pseudotype, could be amplified to titres close to those of native AcMNPV. In contrast, none was able to transduce the Saos-2 and HeLa cell lines. The robust support provided by MacoNPV F in virus production makes the corresponding pseudotype a viable scaffold to display surface ligands to direct selective mammalian cell targeting.
- Published
- 2012
13. Cancer stem cells: in the line of fire
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Linda J. Nicholson, Wey-Ran Lin, Lim Sm, and Malcolm R. Alison
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Genetics ,Cellular differentiation ,Wnt signaling pathway ,Notch signaling pathway ,Cell Differentiation ,General Medicine ,Biology ,Oncology ,Differentiation therapy ,Cancer stem cell ,Neoplasms ,Cancer cell ,Cancer research ,Neoplastic Stem Cells ,Animals ,Humans ,Radiology, Nuclear Medicine and imaging ,Epithelial–mesenchymal transition ,Molecular Targeted Therapy ,Stem cell ,Signal Transduction - Abstract
Most tumours appear to contain a sub-population (s) of self-renewing and expanding stem cells known as cancer stem cells (CSCs). The CSC model proposes that CSCs are at the apex of a hierarchically organized cell population, somewhat akin to normal tissue organization. Selection pressures may also facilitate the stochastic clonal expansion of sub-sets of cancer cells that may co-exist with CSCs and their progeny, moreover the trait of stemness may be more fluid than hitherto expected, and cells may switch between the stem and non-stem cell state. A large body of evidence points to the fact that CSCs are particularly resistant to radiotherapy and chemotherapy. In this review we discuss the basis of such resistance that highlights the roles of ABC transporters, aldehyde dehydrogenase (ALDH) activity, intracellular signalling pathways, the DNA damage response, hypoxia and proliferative quiescence as being significant determinants. In the light of such observations, we outline strategies for the successful eradication of CSCs, including targeting the self-renewal controlling pathways (Wnt, Notch and Hedgehog), ALDH activity and ABC transporters, blocking epithelial mesenchymal transition (EMT), differentiation therapy and niche targeting.
- Published
- 2012
14. Chronic inflammation and hepatocellular carcinoma
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Malcolm R, Alison, Linda J, Nicholson, and Wey-Ran, Lin
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Liver Cirrhosis ,STAT3 Transcription Factor ,Carcinoma, Hepatocellular ,Interleukin-6 ,Stem Cells ,Liver Neoplasms ,NF-kappa B ,Fibrosis ,Hepatitis ,ErbB Receptors ,Interleukin-1alpha ,Hepatocytes ,Neoplastic Stem Cells ,Humans ,Obesity ,Signal Transduction - Abstract
Hepatocellular carcinoma (HCC) invariably develops within a setting of chronic inflammation caused by either hepatotropic viruses, toxins, metabolic liver disease or autoimmunity. Mechanisms that link these two processes are not completely understood, but transcription factors of the NF-κB family and signal transducer and activator of transcription 3 (STAT3), cytokines such as IL-6 and IL-1α and ligands of the epidermal growth factor receptor (EGFR) family are clearly pivotal players. HCC may have its origins in either hepatocytes or hepatic progenitor cells (HPCs), and HCCs, like other solid tumours appear to be sustained by a minority population of cancer stem cells.
- Published
- 2011
15. Chronic Inflammation and Hepatocellular Carcinoma
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Linda J. Nicholson, Malcolm R. Alison, and Wey-Ran Lin
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education.field_of_study ,biology ,business.industry ,Population ,HCCS ,medicine.disease ,digestive system diseases ,Cancer stem cell ,Hepatocellular carcinoma ,biology.protein ,Cancer research ,Medicine ,Epidermal growth factor receptor ,Progenitor cell ,Stem cell ,business ,STAT3 ,education - Abstract
Hepatocellular carcinoma (HCC) invariably develops within a setting of chronic inflammation caused by either hepatotropic viruses, toxins, metabolic liver disease or autoimmunity. Mechanisms that link these two processes are not completely understood, but transcription factors of the NF-κB family and signal transducer and activator of transcription 3 (STAT3), cytokines such as IL-6 and IL-1α and ligands of the epidermal growth factor receptor (EGFR) family are clearly pivotal players. HCC may have its origins in either hepatocytes or hepatic progenitor cells (HPCs), and HCCs, like other solid tumours appear to be sustained by a minority population of cancer stem cells.
- Published
- 2011
16. ABC Transporters, Aldehyde Dehydrogenase, and Adult Stem Cells
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Malcolm R. Alison, Naomi Guppy, and Linda J. Nicholson
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education.field_of_study ,Side population ,biology ,Cancer stem cell ,Population ,biology.protein ,Aldehyde dehydrogenase ,ATP-binding cassette transporter ,Cell sorting ,Stem cell ,education ,Cell biology ,Adult stem cell - Abstract
Despite many years of intensive effort, there is surprisingly little consensus on the most suitable markers with which to locate and isolate stem cells from adult tissues. So-called markers of stem cells have been varied but can be broadly categorized into molecular determinants that govern self-renewal, clonogenicity, multipotentiality, adherence to the niche and longevity. This chapter describes two specific attributes of many stem cells that appear to be the main determinants of stem cell survival, namely either an ability to detoxify many potentially cytotoxic molecules by virtue of high aldehyde dehydrogenase (ALDH) activity or an ability to actively efflux a wide variety of cytotoxic agents by virtue of the presence of one or more ATP-binding cassette transporters (ABC transporters), and indeed many stem cells may be endowed with both properties. Antibodies are available against the ALDH enzyme family and ABC transporters, but the vast majority of studies have used cell sorting techniques to enrich for cells expressing these molecules. Live cells expressing high ALDH activity are usually identified by the ALDEFLUOR kit and sorted by fluorescence-activated cell sorting (FACS), the latter technique is also being used to isolate cells with high ABC transporter activity after incubation with a fluorescent dye (usually Hoechst 33342) that is actively effluxed from these cells giving rise to a fluorescent dull population known as the “side population”. Since both ALDH and ABC transporter activities are cytoprotective strategies, it is not surprising that many cancer stem cells have these mechanisms working robustly, but they are also present in normal adult stem cells. This chapter critically reviews ALDH activity and the SP as markers of normal adult stem cells.
- Published
- 2011
17. Arginine deprivation and argininosuccinate synthetase expression in the treatment of cancer
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Tim Crook, Barbara Delage, Peter W. Szlosarek, Iain A. McNeish, Dean A. Fennell, Nicholas R. Lemoine, and Linda J. Nicholson
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Cancer Research ,biology ,Arginine ,Auxotrophy ,Argininosuccinate synthase ,Cancer ,Methylation ,Argininosuccinate Synthase ,Prognosis ,medicine.disease ,Molecular biology ,Arginase ,Oncology ,Downregulation and upregulation ,Neoplasms ,Cancer research ,biology.protein ,medicine ,Animals ,Humans ,Arginine deiminase - Abstract
Arginine, a semi-essential amino acid in humans, is critical for the growth of human cancers, particularly those marked by de novo chemoresistance and a poor clinical outcome. In addition to protein synthesis, arginine is involved in diverse aspects of tumour metabolism, including the synthesis of nitric oxide, polyamines, nucleotides, proline and glutamate. Tumoural downregulation of the enzyme argininosuccinate synthetase (ASS1), a recognised rate-limiting step in arginine synthesis, results in an intrinsic dependence on extracellular arginine due to an inability to synthesise arginine for growth. This dependence on extracellular arginine is known as arginine auxotrophy. Several tumours are arginine auxotrophic, due to variable loss of ASS1, including hepatocellular carcinoma, malignant melanoma, malignant pleural mesothelioma, prostate and renal cancer. Importantly, targeting extracellular arginine for degradation in the absence of ASS1 triggers apoptosis in arginine auxotrophs. Several phase I/II clinical trials of the arginine-lowering drug, pegylated arginine deiminase, have shown encouraging evidence of clinical benefit and low toxicity in patients with ASS1-negative tumours. In part, ASS1 loss is due to epigenetic silencing of the ASS1 promoter in various human cancer cell lines and tumours, and it is this silencing that confers arginine auxotrophy. In relapsed ovarian cancer, this is associated with platinum refractoriness. In contrast, several platinum sensitive tumours, including primary ovarian, stomach and colorectal cancer, are characterised by ASS1 overexpression, which is regulated by proinflammatory cytokines. This review examines the prospects for novel approaches in the prevention, diagnosis and treatment of malignant disease based on ASS1 pathophysiology and its rate-limiting product, arginine.
- Published
- 2010
18. Epigenetic inactivation implies independent functions for insulin-like growth factor binding protein (IGFBP)-related protein 1 and the related IGFBPL1 in inhibiting breast cancer phenotypes
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Marcella Occelli, Linda J. Nicholson, Ornella Garrone, Nelofer Syed, Paul D. Smith, Louise Hiller, Tim Crook, Milena Gasco, and Annette M. Payne
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Cancer Research ,medicine.medical_specialty ,Breast Neoplasms ,Insulin-like growth factor-binding protein ,Epigenesis, Genetic ,Breast cancer ,Internal medicine ,Cell Line, Tumor ,medicine ,Humans ,Sulfites ,Epigenetics ,Regulation of gene expression ,biology ,Base Sequence ,Reverse Transcriptase Polymerase Chain Reaction ,Tumor Suppressor Proteins ,Cancer ,Methylation ,DNA, Neoplasm ,DNA Methylation ,medicine.disease ,Gene Expression Regulation, Neoplastic ,Insulin-Like Growth Factor Binding Protein 1 ,Insulin-Like Growth Factor Binding Proteins ,Endocrinology ,Treatment Outcome ,Oncology ,CpG site ,DNA methylation ,Cancer research ,biology.protein ,Female - Abstract
Purpose: To analyze epigenetic regulation of two related genes, insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) and IGFBPL1, and its significance as a determinant of clinical phenotypes in human breast cancer. Experimental Design: We have investigated the expression and epigenetic regulation of IGFBP-rP1 and IGFBPL1 in human breast cancer cell lines and primary and metastatic carcinomas. Results: Expression of IGFBP-rP1 and IGFBPL1 is down-regulated in breast cancer cell lines. Aberrant methylation in the CpG islands of each gene correlates well with loss of expression at the mRNA level. Analysis of methylation in DNA isolated from human primary breast tumors showed that methylation in either gene was associated with a worse overall survival (OS; P = 0.008) and disease-free survival (DFS) following surgery (P = 0.04) and worse DFS following adjuvant chemotherapy (P = 0.01). Methylation of IGFBP-rP1 alone was associated with a trend toward decreased OS (P = 0.10) and decreased DFS (P = 0.25). Methylation in IGFBPL1 was clearly associated with worse OS (P = 0.001) and DFS (P < 0.0001). Methylation in either IGFBP-rP1 or IGFBPL1 was significantly associated with nodal disease (P < 0.001). Conclusions: Expression of IGFBP-rP1 and IGFBPL1 is regulated by aberrant hypermethylation in breast cancer, implying that inactivation of these genes is involved in the pathogenesis of this malignancy. Analysis of methylation of these genes may have utility in prediction of clinical phenotypes, such as nodal disease and response to chemotherapy.
- Published
- 2007
19. RNA interference mediated in human primary cells via recombinant baculoviral vectors
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Alan J. Paine, Derek A. Mann, Linda J. Nicholson, Marie Philippe, and Colin T. Dolphin
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Small interfering RNA ,viruses ,Genetic Vectors ,Green Fluorescent Proteins ,Gene Expression ,Gene delivery ,Biology ,Viral vector ,Cell Line ,Small hairpin RNA ,Transduction (genetics) ,RNA interference ,Transduction, Genetic ,Drug Discovery ,Genetics ,Humans ,RNA, Small Interfering ,Molecular Biology ,Pharmacology ,Gene knockdown ,Transfection ,Virology ,Hepatocytes ,Molecular Medicine ,RNA Interference ,Baculoviridae - Abstract
The success of RNA interference (RNAi) in mammalian cells, mediated by siRNAs or shRNA-generating plasmids, is dependent, to an extent, upon transfection efficiency. This is a particular problem with primary cells, which are often difficult to transfect using cationic lipid vehicles. Effective RNAi in primary cells is thus best achieved with viral vectors, and retro-, adeno-, and lentivirus RNAi systems have been described. However, the use of such human viral vectors is inherently problematic, e.g., Class 2 status and requirement of secondary helper functions. Although insect cells are their natural host, baculoviruses also transduce a range of vertebrate cell lines and primary cells with high efficiency. The inability of baculoviral vectors to replicate in mammalian cells, their Class 1 status, and the simplicity of their construction make baculovirus an attractive alternative gene delivery vector. We have developed a baculoviral-based RNAi system designed to express shRNAs and GFP from U6 and CMV promoters, respectively. Transduction of Saos2, HepG2, Huh7, and primary human hepatic stellate cells with a baculoviral construct expressing shRNAs targeting lamin A/C resulted in effective knockdown of the corresponding mRNA and protein. Development of this baculoviral-based system provides an additional shRNA delivery option for RNAi-based investigations in mammalian cells.
- Published
- 2004
20. Role of Epstein-Barr virus gene latent membrane protein in nasopharyngeal carcinoma
- Author
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Jonathan D.H. Morris and Linda J. Nicholson
- Subjects
Microbiology (medical) ,Herpesvirus 4, Human ,Nasopharyngeal Neoplasms ,Oncogene Proteins, Viral ,Biology ,medicine.disease_cause ,medicine.disease ,Microbiology ,Virology ,Epstein–Barr virus ,Viral Matrix Proteins ,Infectious Diseases ,Membrane protein ,Nasopharyngeal carcinoma ,medicine ,Animals ,Humans ,Gene - Published
- 1996
21. Oral Presentations 5
- Author
-
Richard Camplejohn, Linda J. Nicholson, Ian R. Hart, and H W Chng
- Subjects
Tumor angiogenesis ,Cancer Research ,Oncology ,business.industry ,Cancer research ,Oral Presentation ,Medicine ,business - Published
- 2004
22. Counter-selection recombineering of the baculovirus genome: a strategy for seamless modification of repeat-containing BACs
- Author
-
Derek A. Mann, Linda J. Nicholson, Marcel Westenberg, Colin T. Dolphin, and Helen M. Soedling
- Subjects
Chromosomes, Artificial, Bacterial ,Genome, Viral ,Biology ,Genome ,Homology (biology) ,Recombineering ,Cell Line ,Recombinases ,03 medical and health sciences ,chemistry.chemical_compound ,Transduction (genetics) ,Transduction, Genetic ,Escherichia coli ,Genetics ,Recombinase ,Animals ,Humans ,Gene ,Repetitive Sequences, Nucleic Acid ,030304 developmental biology ,Recombination, Genetic ,0303 health sciences ,030302 biochemistry & molecular biology ,Fosmid ,chemistry ,Methods Online ,Genetic Engineering ,Baculoviridae ,DNA - Abstract
Recombineering is employed to modify large DNA clones such as fosmids, BACs and PACs. Subtle and seamless modifications can be achieved using counter-selection strategies in which a donor cassette carrying both positive and negative markers inserted in the target clone is replaced by the desired sequence change. We are applying counter-selection recombineering to modify bacmid bMON14272, a recombinant baculoviral genome, as we wish to engineer the virus into a therapeutically useful gene delivery vector with cell targeting characteristics. Initial attempts to replace gp64 with Fusion (F) genes from other baculoviruses resulted in many rearranged clones in which the counter-selection cassette had been deleted. Bacmid bMON14272 contains nine highly homologous regions (hrs) and deletions were mapped to recombination between hr pairs. Recombineering modifications were attempted to decrease intramolecular recombination and/or increase recombineering efficiency. Of these only the use of longer homology arms on the donor molecule proved effective permitting seamless modification. bMON14272, because of the presence of the hr sequences, can be considered equivalent to a highly repetitive BAC and, as such, the optimized method detailed here should prove useful to others applying counter-selection recombineering to modify BACs or PACs containing similar regions of significant repeating homologies.
- Published
- 2010
23. Gender Justice without Foundations
- Author
-
Marion Smiley, Iris Marion Young, and Linda J. Nicholson
- Subjects
Gender justice ,Sociology ,Criminology ,Postmodernism ,Law ,Economic Justice ,Feminism - Published
- 1991
24. Fibronectin-keratinocyte interactions during terminal differentiation
- Author
-
Linda J. Nicholson, Fiona M. Watt, and Josephine C. Adams
- Subjects
Fibronectin ,medicine.anatomical_structure ,biology ,Terminal (electronics) ,Chemistry ,biology.protein ,medicine ,Cell Biology ,Keratinocyte ,Cell biology - Published
- 1990
25. Comment on Rosaldo's 'The Use and Abuse of Anthropology'
- Author
-
Linda J. Nicholson
- Subjects
Gender Studies ,Arts and Humanities (miscellaneous) ,Anthropology ,Sociology - Published
- 1982
26. 'The Personal is Political'
- Author
-
Linda J. Nicholson
- Subjects
Politics ,Political science ,Environmental ethics ,General Medicine ,Applied philosophy - Published
- 1981
27. What Schooling in Capitalist America Teaches Us about Philosophy
- Author
-
Linda J. Nicholson
- Subjects
Philosophy ,Contemporary philosophy ,Work (electrical) ,Mainstream ,Sociology ,Philosophy of education ,Epistemology - Abstract
As a philosopher working in the area of education, I believe Samuel Bowles’ and Herbert Gintis’ recent book, Schooling in Capitalist America1 to be an important work. I believe it to be important first of all for the concrete ideas it raises about education in the history and present reality of American society. Secondly, it serves as an excellent example in a lesson in what philosophy, both philosophy of education, and philosophy generally, ought to become. In particular, by contrasting this work in its conclusions and methods with other works in mainstream contemporary philosophy of education, I believe we can see more clearly certain defects in contemporary philosophy of education, which apply also to other fields in philosophy. To accomplish this goal, I would like first of all to summarize the book itself.The aim of Schooling in Capitalist America is to expose many of those self-deceptions which our society has about itself and its educational system.
- Published
- 1978
28. The Marxist Theory of Schooling
- Author
-
Linda J. Nicholson
- Subjects
Philosophy ,Marxist philosophy ,Sociology ,Social science ,Epistemology - Published
- 1983
29. Chapter Six. Karl Marx: The Theoretical Separation of the Domestic and the Economic
- Author
-
Linda J. Nicholson
- Subjects
Separation (statistics) ,Sociology ,Neoclassical economics - Published
- 1986
30. Chapter Five. John Locke: The Theoretical Separation of the Family and the State
- Author
-
Linda J. Nicholson
- Subjects
State (polity) ,media_common.quotation_subject ,Separation (statistics) ,Sociology ,media_common ,Epistemology - Published
- 1986
31. Gender and History
- Author
-
Linda J. Nicholson
- Published
- 1986
32. Chapter Four. Gender and Modernity: Reinterpreting the Family, the State, and the Economy
- Author
-
Linda J. Nicholson
- Subjects
State (polity) ,media_common.quotation_subject ,Modernity ,Political economy ,Sociology ,media_common - Published
- 1986
33. Chapter Seven. Conclusion
- Author
-
Linda J. Nicholson
- Subjects
Sociology ,Social science - Published
- 1986
34. Chapter Two. From Suffrage to Sexuality
- Author
-
Linda J. Nicholson
- Subjects
Suffrage ,Gender studies ,Human sexuality ,Sociology - Published
- 1986
35. Declogging small-bore feeding tubes
- Author
-
Linda J. Nicholson
- Subjects
Bromelain (pharmacology) ,030309 nutrition & dietetics ,Medicine (miscellaneous) ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,food ,Enteral Nutrition ,Medicine ,Humans ,Therapeutic Irrigation ,Intubation, Gastrointestinal ,Syringe ,food.beverage ,Food, Formulated ,0303 health sciences ,Nutrition and Dietetics ,Chromatography ,Chymotrypsin ,biology ,business.industry ,CRANBERRY JUICE ,Water pressure ,Papain ,Equipment failure ,chemistry ,Biochemistry ,Distilled water ,biology.protein ,030211 gastroenterology & hepatology ,Equipment Failure ,business - Abstract
Nine substances (Pancrease, Viokase, pork pancreatin, bromelain, papain, cranberry juice, Coca-Cola, chymotrypsin, and distilled water) were tested every half-hour for 4 hr using 900 mm of water pressure to determine their effectiveness in declogging small-bore feeding tubes. At the end of 4 hr the tubes were irrigated with air using a 50-cc syringe. None of the substances tested were effective within 4 hr. Three substances allowed for successful syringe irrigation at the end of 4 hr. They were: chymotrypsin, papain, and distilled water.
- Published
- 1987
36. Effects of sodium cyclamate and sodium saccharin on focus induction in explant cultures of rat bladder
- Author
-
Linda J. Nicholson and Harsha Jani
- Subjects
Cyclamates ,Cancer Research ,Urinary bladder ,Focus (geometry) ,Sodium cyclamate ,Urinary Bladder ,Methylnitrosourea ,Pharmacology ,Rats, Inbred F344 ,Rats ,chemistry.chemical_compound ,medicine.anatomical_structure ,Saccharin ,Oncology ,chemistry ,Biochemistry ,SODIUM SACCHARIN ,medicine ,Animals ,Female ,Rat Bladder ,Carcinogen ,Cells, Cultured ,Explant culture - Abstract
The tumour-promoting activities of sodium cyclamate and sodium saccharin were investigated in an assay based on the induction of epithelial foci exhibiting enhanced growth potential in a rat bladder explant culture system. An initiating, non-focus-inducing dose was defined for the carcinogen N-methyl-N-nitrosourea (MNU) to make promotion studies possible. Saccharin induced epithelial foci when added to cultures pretreated with an initiating dose of MNU, and also increased the incidence of foci in cultures treated with transforming doses of MNU. Cyclamate was found to induce a high incidence of foci when added to cultures by itself. When MNU and cyclamate treatments were combined, an additive effect could be detected. These results indicate that both cyclamate and saccharin can contribute to epithelial transformation in this system.
- Published
- 1988
37. Jane Roland Martin., Reclaiming a Conversation: The Ideal of the Educated Woman
- Author
-
Linda J. Nicholson
- Subjects
Philosophy ,Ideal (set theory) ,Psychoanalysis ,media_common.quotation_subject ,Conversation ,Sociology ,media_common - Published
- 1989
38. Discovering Reality
- Author
-
Linda J. Nicholson
- Subjects
Philosophy ,medicine.medical_specialty ,Philosophy of science ,Social epistemology ,medicine ,Epistemology of Wikipedia ,Metaphysics ,Western philosophy ,Feminist philosophy ,Epistemology - Published
- 1987
39. Gender and History; The Limits of Social Theory in the Age of the Family. By Linda J. Nicholson (New York: Columbia University Press, 1986. 238p. $29.00). - Feminism and Equality. Edited by Anne Phillips (New York: New York University Press, 1987. 202p. $35.00, cloth; $15.00, paper)
- Author
-
Linda J. Nicholson, Anne Phillips, and Mary Lyndon Shanley
- Subjects
Sociology and Political Science ,Political Science and International Relations ,Gender studies ,Sociology ,Social science ,Gender history ,Feminism ,Social theory - Published
- 1988
40. Ricca Edmundson., Rhetoric in Sociology
- Author
-
Linda J. Nicholson
- Subjects
Philosophy ,media_common.quotation_subject ,Rhetoric ,Sociology ,Classics ,media_common - Published
- 1989
41. Self, Society and Womankind
- Author
-
Linda J. Nicholson
- Subjects
Dialectic ,Philosophy ,Psychoanalysis ,Sociology - Published
- 1983
42. Making Our Marx
- Author
-
Linda J. Nicholson and Lise Vogel
- Published
- 1984
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