R C Rees

Nottingham Trent University, Nottigham, England, United Kingdom

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Publications (273)943.8 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The expression of HAGE as a novel prognostic and predictive tool was assessed in 1079 TNBCs. HAGE protein expression was investigated in an early primary TNBC (EP-TNBC; n=520) cohort who received adjuvant chemotherapy (ACT) and in a locally advanced primary TNBC cohort who received anthracycline-combination Neo-ACT (n=110; AC-Neo-ACT). HAGE-mRNA expression was evaluated in the METABRIC-TNBC-cohort (n=311) who received ACT and in a cohort of patients with TNBC who received doxorubicin/cyclophosphamide Neo-ACT, followed by 1:1 randomisation to ixabepilone (n=68) or paclitaxel (n=64) as part of a phase II clinical trial. Furthermore, a cohort of 128 tumours with integrated HAGE gene copy number changes, mRNA and protein levels were analysed. In patients with EP-TNBC, who were chemotherapy-naïve, high HAGE protein expression (HAGE+) was associated with a higher risk of death (HR: 1.3; 95% CI: 1.2-1.5; p=0.000005) when compared HAGE- cases. Patients who received ACT and expressed mRNA-HAGE+ were at a lower risk of death than those who were mRNA-HAGE- (p=0.004). The expression of HAGE was linked to the presence of tumour infiltrating lymphocytes (TILs), and both features were found to be independent predictors for pathological complete response (pCR, ps<0.001) and associated with prolonged survival (ps<0.01), following AC-Neo-ACT. In patients with residual disease, HAGE+ had a two-fold death risk increase (p=0.018) compared to HAGE-. HAGE expression is a potential prognostic marker and a predictor of response to anthracycline treatment in TNBC. A prospective clinical trial to examine the therapeutic value of HAGE for TNBC cases is warranted. Copyright © 2015, American Association for Cancer Research.
    Clinical Cancer Research 08/2015; DOI:10.1158/1078-0432.CCR-15-0610 · 8.72 Impact Factor
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    ABSTRACT: The expected five-year survival rate from a stage III ovarian cancer diagnosis is a mere 22%; this applies to the 7000 new cases diagnosed yearly in the UK. Stratification of patients with this heterogeneous disease, based on active molecular pathways, would aid a targeted treatment improving the prognosis for many cases. While hundreds of genes have been associated with ovarian cancer, few have yet been verified by peer research for clinical significance. Here, a meta-analysis approach was applied to two carefully selected gene expression microarray datasets. Artificial neural networks, Cox univariate survival analyses and T-tests identified genes whose expression was consistently and significantly associated with patient survival. The rigor of this experimental design increases confidence in the genes found to be of interest. A list of 56 genes were distilled from a potential 37,000 to be significantly related to survival in both datasets with a FDR of 1.39859 × 10−11, the identities of which both verify genes already implicated with this disease and provide novel genes and pathways to pursue. Further investigation and validation of these may lead to clinical insights and have potential to predict a patient’s response to treatment or be used as a novel target for therapy.
    07/2015; 4(3):324-338. DOI:10.3390/microarrays4030324
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    ABSTRACT: Background and Objectives Advantages of using cord blood (CB) over other sources of haematopoietic progenitor cells, such as bone marrow, include the ability to cryopreserve and bank the samples until requested for a transplant. Cryopreservation requires the addition of a cryoprotectant to prevent the formation of intracellular ice during freezing. Dimethyl sulphoxide (DMSO) is commonly used at a concentration of 10% (v/v); however, there is evidence to suggest this chemical is toxic to cells as well as to patients after infusion.Materials and Methods The toxic effects of DMSO were assessed through cell viability and in vitro functional assays in fresh and post-thaw CB samples before determining the maximum exposure time and optimal concentration for cryopreservation.ResultsA dose-dependent toxicity of DMSO was observed in fresh samples with 40% removing all viable and functional haematopoietic progenitor cells (HPC). In fresh and post-thaw analysis, minimal toxic effect was observed when cryopreservation was delayed for up to 1 h after 10% DMSO addition. After thawing, DMSO washout was superior to dilution or unmanipulated when maintained for long periods (advantage observed 1 h after thawing). Finally, the optimum concentration for cryopreserving CB was found to be 7·5 to 10% with detrimental effects observed outside of this range.Conclusion These results support the use of 7·5–10% as the optimal DMSO concentration and the maximum exposure time should be limited to <1 h prior to freezing and 30 min post-thaw.
    Vox Sanguinis 04/2015; 109(2). DOI:10.1111/vox.12267 · 2.80 Impact Factor
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    ABSTRACT: Developing materials that can preferentially select defined cancer cell populations for biological characterization will greatly enhance our understanding of cancer cell growth, differentiation, and invasion. The transitional events between epithelial and mesenchymal phenotypes are particularly crucial, as primary tumors and secondary metastasis are generally epithelial in nature, whereas circulating mesenchymal cells derived from primary epithelial cells appear to facilitate the spread of disease and its resistance to therapy. This study describes an amino-functionalized material, which promotes the enrichment of an epithelial phenotype from a single cell line containing both epithelial and mesenchymal subpopulations of cancer cells. The isolation and transitional control of such subpopulations using functional materials will advance understanding of the disease process, have a significant impact on the downstream development of new targeted cancer therapeutics, and also be applicable to tissue engineering and regenerative medicine.
    Advanced Healthcare Materials 03/2015; 4(4). DOI:10.1002/adhm.201400525 · 5.80 Impact Factor
  • 1 edited by Nima Rezaei, 01/2015; Springer-Verlag Berlin Heidelberg., ISBN: 978-3-662-44945-5
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    ABSTRACT: The aim of the immunotherapy and peptide therapeutics is to destroy cancer cells without eliciting lethal side effects and sustain the long-lasting immune memory. Targeting major histocompatibility complex (MHC) class I and class II epitopes and multiple tumor antigens has met with some clinical success, which is advantageous over single epitope vaccine strategies. Moreover, cancer immunotherapy and peptide therapeutics especially have demonstrated improved responses over that of the conventional treatments in patient groups where treatment options are limited. However, there are still obstacles to combating advanced cancer, where the immune system of the host is compromised. Thus implementing ways of overcoming states of immune tolerance, anergy, or suppression concomitant with a vaccine strategy to enhance adaptive immunity offers an attractive route for clinical intervention. Targeted therapies against defined tumor antigens involving the use of peptide-based vaccination offer potential for the future. Novel therapeutics relies on knowledge of peptide epitopes and awareness of how these can be used to activate appropriate tumor immunity. In this review we discuss many of the tumor antigens that have been discovered in the past two decades and their clinical utility alongside conventional cancer therapies.
    Cancer Immunology, 01/2015: pages 55-71; , ISBN: 978-3-662-44945-5
  • Bioinformatics and Biomedicine (BIBM), 2014 IEEE International Conference on; 11/2014
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    ABSTRACT: Under normal conditions the detachment of anchorage-dependant cells from their extracellular matrix typically induces programmed cell death which is mediated through a pathway referred to as anoikis. However, a resistance to anoikis in cancer enables the migration of cells from the primary tumour and the establishment of aggressive metastatic disease. Although cancer cell aggregation is known to be an important mechanism within anoikis resistance, research into the underlying mechanisms that govern this process remain problematic as commercially available tissue culture material can only sustain 2D monolayer or 3D aggregate/spheroid cultures. This necessitates the development of a system that can accommodate for cancer cell aggregation–disaggregation as a single dynamic process, without the disruption of passaging cells between alternate substrates. This study describes a procedure for modifying tissue culture polystyrene (TCP) to produce a fluoro-silica (FS) surface which preferentially promotes the deposition of a distinct profile of proteins/factors from serum which mediate the transient aggregation of human breast cancer cell lines. This modified surface therefore provides an experimental platform for better understanding cancer cell aggregation–disaggregation events in vitro, and their influence on the establishment of metastatic disease in patients with cancer.
    07/2014; 2(10). DOI:10.1039/C4BM00194J
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    ABSTRACT: Background: HAGE protein is a known immunogenic cancer-specific antigen. Methods: The biological, prognostic and predictive values of HAGE expression was studied using immunohistochemistry in three cohorts of patients with BC (n=2147): early primary (EP-BC; n=1676); primary oestrogen receptor-negative (PER-BC; n=275) treated with adjuvant anthracycline-combination therapies (Adjuvant-ACT); and primary locally advanced disease (PLA-BC) who received neo-adjuvant anthracycline-combination therapies (Neo-adjuvant-ACT; n=196). The relationship between HAGE expression and the tumour-infiltrating lymphocytes (TILs) in matched prechemotherapy and postchemotherapy samples were investigated. Results: Eight percent of patients with EP-BC exhibited high HAGE expression (HAGE+) and was associated with aggressive clinico-pathological features (Ps<0.01). Furthermore, HAGE+expression was associated with poor prognosis in both univariate and multivariate analysis (Ps<0.001). Patients with HAGE+did not benefit from hormonal therapy in high-risk ER-positive disease. HAGE+and TILs were found to be independent predictors for pathological complete response to neoadjuvant-ACT; P<0.001. A statistically significant loss of HAGE expression following neoadjuvant-ACT was found (P=0.000001), and progression-free survival was worse in those patients who had HAGE+residual disease (P=0.0003). Conclusions: This is the first report to show HAGE to be a potential prognostic marker and a predictor of response to ACT in patients with BC.
    British Journal of Cancer 04/2014; 110(10). DOI:10.1038/bjc.2014.168 · 4.84 Impact Factor
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    ABSTRACT: A stage III ovarian cancer diagnosis yields a 22% 5-year survival rate, this applies to over half of the 7000 new cases diagnosed each year in the UK. Stratification of patients with this heterogeneous disease, based on active molecular pathways in their cancer, would aid a targeted treatment and improve prognosis. Hundreds of genes have been significantly associated with ovarian cancer, few have yet been verified. Exploration of published microarray data sets using Artificial Neural Networks confirmed the robustness of PRELP as a biomarker for survival time from stage III ovarian cancer, and generated a new panel of 44 genes that significantly predicted survival length of a blind valida-tion set (p=0.00073).
    Proceedings of the international work-conference on Bioinformatics and Biomedical Engineering (IWBBIO 2014), Granada Spain; 04/2014
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    ABSTRACT: Treatment options for patients with advanced prostate cancer remain limited and rarely curative. Prostatic acid phosphatase (PAP) is a prostate-specific protein over-expressed in 95% of prostate tumours. An FDA-approved vaccine for the treatment of advanced prostate disease, PROVENGE® (sipuleucel-T), has been shown to prolong survival, however the precise sequence of the PAP protein responsible for the outcome is unknown. As the PAP antigen is one of the very few prostate-specific antigens for which there is a rodent equivalent with high homology, pre-clinical studies using PAP have the potential to be directly relevant to clinical setting. Here we show three PAP epitopes naturally processed and presented in the context of HHDII/DR1 (114-128, 299-313, and 230-244). The PAP-114-128 epitope elicits CD4(+) and CD8(+) T-cell-specific responses in C57BL/6 mice. Furthermore, when immunised in a DNA vector format (ImmunoBody®), PAP-114-128 prevents and reduces the growth of TRAMP-C1 prostate cancer cell-derived tumours in both prophylactic and therapeutic settings. This anti-tumour effect is associated with infiltration of CD8(+) tumour-infiltrating lymphocytes (TILs) and the generation of high avidity T cells secreting elevated levels of IFN-γ. PAP-114-128 therefore appears to be a highly relevant peptide on which to base vaccines for the treatment of prostate cancer. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 04/2014; 44(4). DOI:10.1002/eji.201343863 · 4.03 Impact Factor
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    ABSTRACT: The tumour suppressor PML (promyelocytic leukaemia protein) regulates several cellular pathways involving cell growth, apoptosis, differentiation and senescence. PML also has an important role in the regulation of stem cell proliferation and differentiation. Here, we show the involvement of the helicase HAGE in the transcriptional repression of PML expression in ABCB5+ malignant melanoma-initiating cells (ABCB5+ MMICs), a population of cancer stem cells which are responsible for melanoma growth, progression and resistance to drug-based therapy. HAGE prevents PML gene expression by inhibiting the activation of the JAK-STAT (janus kinase-signal transducers and activators of transcription) pathway in a mechanism which implicates the suppressor of cytokine signalling 1 (SOCS1). Knockdown of HAGE led to a significant decrease in SOCS1 protein expression, activation of the JAK-STAT signalling cascade and a consequent increase of PML expression. To confirm that the reduction in SOCS1 expression was dependent on the HAGE helicase activity, we showed that SOCS1, effectively silenced by small interfering RNA, could be rescued by re-introduction of HAGE into cells lacking HAGE. Furthermore, we provide a mechanism by which HAGE promotes SOCS1 mRNA unwinding and protein expression in vitro. Finally, using a stem cell proliferation assay and tumour xenotransplantation assay in non-obese diabetic/severe combined immunodeficiency mice, we show that HAGE promotes MMICs-dependent tumour initiation and tumour growth by preventing the anti-proliferative effects of interferon-α (IFNα). Our results suggest that the helicase HAGE has a key role in the resistance of ABCB5+ MMICs to IFNα treatment and that cancer therapies targeting HAGE may have broad implications for the treatment of malignant melanoma.
    Cell Death & Disease 02/2014; 5(2):e1061. DOI:10.1038/cddis.2014.29 · 5.01 Impact Factor
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    ABSTRACT: Vaccine-based immunotherapy can increase the overall survival of patients with advanced prostate cancer. However, the efficacy of vaccine-elicited anticancer immune responses is heavily influenced by the physical, nutritional, and psychological status of the patient. Given their importance, these parameters should be carefully considered for the design of future clinical trials testing this immunotherapeutic paradigm in prostate cancer patients.
    OncoImmunology 02/2014; 3(3):e28049. DOI:10.4161/onci.28049 · 6.27 Impact Factor
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    ABSTRACT: Oestrogen receptor (ER) positive (luminal) tumours account for the largest proportion of females with breast cancer. Theirs is a heterogeneous disease presenting clinical challenges in managing their treatment. Three main biological luminal groups have been identified but clinically these can be distilled into two prognostic groups in which Luminal A are accorded good prognosis and Luminal B correlate with poor prognosis. Further biomarkers are needed to attain classification consensus. Machine learning approaches like Artificial Neural Networks (ANNs) have been used for classification and identification of biomarkers in breast cancer using high throughput data. In this study, we have used an artificial neural network (ANN) approach to identify DACH1 as a candidate luminal marker and its role in predicting clinical outcome in breast cancer is assessed. A reiterative ANN approach incorporating a network inferencing algorithm was used to identify ER-associated biomarkers in a publically available cDNA microarray dataset. DACH1 was identified in having a strong influence on ER associated markers and a positive association with ER. Its clinical relevance in predicting breast cancer specific survival was investigated by statistically assessing protein expression levels after immunohistochemistry in a series of unselected breast cancers, formatted as a tissue microarray. Strong nuclear DACH1 staining is more prevalent in tubular and lobular breast cancer. Its expression correlated with ER-alpha positive tumours expressing PgR, epithelial cytokeratins (CK)18/19 and 'luminal-like' markers of good prognosis including FOXA1 and RERG (p<0.05). DACH1 is increased in patients showing longer cancer specific survival and disease free interval and reduced metastasis formation (p<0.001). Nuclear DACH1 showed a negative association with markers of aggressive growth and poor prognosis. Nuclear DACH1 expression appears to be a Luminal A biomarker predictive of good prognosis, but is not independent of clinical stage, tumour size, NPI status or systemic therapy.
    PLoS ONE 01/2014; 9(1):e84428. DOI:10.1371/journal.pone.0084428 · 3.23 Impact Factor
  • Robert Rees
    09/2013; 2(3):25. DOI:10.3978/j.issn.2304-3865.2013.01.01
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    ABSTRACT: The effect of alterations in virulence and transformation by long term in vitro culture of L. mexicana promastigotes on infectivity and immune responses was investigated. Fresh parasite cultures harvested from Balb/c mice were passaged 20 times in vitro. Infectivity was decreased and was completely avirulent after 20 passages. The qPCR results showed a down regulation of GP63, LPG2, CPC, CPB2, CPB2.8, CHT1, LACK and LDCEN3 genes after passage 7 concomitant with a reduced and absence of infectivity by passages 7 and 20, respectively. Parasites at passages 1 and 20 are referred to as virulent and avirulent, respectively. The growth of avirulent and virulent parasite was affected by conditioned media derived from macrophages or monocytes infected with parasites for 2 hours. Giemsa staining showed the failure of avirulent but not virulent parasites to transform to the amastigote stage in infected host cells. with both virulent and avirulent modulating the expression of CCL-22, Tgad51, Cox2, IL-1, IL-10, TGF-β, TNF-α, Rab7, Rab9 and A2 genes; virulent but not avirulent L. mexicana significantly up regulated Th2 associated cytokines, but down regulated Rab7and Rab9 gene expression. In conclusion, a model for L. mexicana is reported, which is of potential value in studying host- parasite interaction. This article is protected by copyright. All rights reserved.
    Parasite Immunology 07/2013; 35(12). DOI:10.1111/pim.12056 · 2.14 Impact Factor
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    ABSTRACT: Breast cancer is a heterogeneous and complex disease. Although the use of tumor biomarkers has improved individualized breast cancer care, i.e., assessment of risk, diagnosis, prognosis, and prediction of treatment outcome, new markers are required to further improve patient clinical management. In the present study, a search for novel breast cancer-associated genes was performed by mining the UniGene database for expressed sequence tags (ESTs) originating from human normal breast, breast cancer tissue, or breast cancer cell lines. Two hundred and twenty-eight distinct breast-associated UniGene Clusters (BUC1-228) matched the search criteria. Four BUC ESTs (BUC6, BUC9, BUC10, and BUC11) were subsequently selected for extensive in silico database searches, and in vitro analyses through sequencing and RT-PCR based assays on well-characterized cell lines and tissues of normal and cancerous origin. BUC6, BUC9, BUC10, and BUC11 are clustered on 10p11.21-12.1 and showed no homology to any known RNAs. Overall, expression of the four BUC transcripts was high in normal breast and testis tissue, and in some breast cancers; in contrast, BUC was low in other normal tissues, peripheral blood mononuclear cells (PBMCs), and other cancer cell lines. Results to-date suggest that BUC11 and BUC9 translate to protein and BUC11 cytoplasmic and nuclear protein expression was detected in a large cohort of breast cancer samples using immunohistochemistry. This study demonstrates the discovery and expression analysis of a tissue-restricted novel transcript set which is strongly expressed in breast tissue and their application as clinical cancer biomarkers clearly warrants further investigation. © 2012 Wiley Periodicals, Inc..
    Genes Chromosomes and Cancer 03/2013; 52(3). DOI:10.1002/gcc.22031 · 4.04 Impact Factor
  • Cancer Research 12/2012; 72(24 Supplement):P6-07-09-P6-07-09. DOI:10.1158/0008-5472.SABCS12-P6-07-09 · 9.33 Impact Factor
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    ABSTRACT: Background: Conditions for maintaining hematopoietic progenitor cells (HPCs) before cryopreservation remain controversial. An understanding of the impact of time and temperature during nonfrozen storage can contribute to the maintenance of the quality of products, improving transplantation outcomes. The objective of this study was to determine the influence on cell potency of thawed products from three sources of HPCs after prolonged storage at different temperatures before cryopreservation. Study design and methods: Viable cell counts by flow cytometry and colony-forming unit (CFU) recoveries were assessed on cord blood (CB), mobilized peripheral blood stem cell (PBSC), and bone marrow (BM) samples over 72 hours using two different storage conditions, refrigerated (4-8°C) or room temperature (19-22°C). To determine the effects of delayed freezing on progenitor recoveries, paired samples were evaluated before and after cryopreservation. Results: All samples maintained at refrigerated temperatures resulted in higher recoveries than those at room temperature in all variables assessed. Specifically, when assessing for CFU yields after thawing, the impact of time on BM resulted in a significant loss as soon as 24 hours (n = 10, 36.4 ± 28.0%, p = 0.003). This decrease was also observed for PBSCs and CB but at 48 hours of fresh storage (PBSCs n = 11, 32.7 ± 26.2%, p = 0.006; CB n = 10, 39.6 ± 26.4%, p = 0.001). Conclusion: Our data suggest that HPC products are better maintained at refrigerated temperatures before cryopreservation. Delaying cryopreservation should be minimized to avoid significant losses in cell potency.
    Transfusion 12/2012; 53(8). DOI:10.1111/trf.12006 · 3.23 Impact Factor
  • Robert C. Rees
    Cancer Immunology and Immunotherapy 09/2012; 61(11). DOI:10.1007/s00262-012-1352-z · 3.94 Impact Factor

Publication Stats

6k Citations
943.80 Total Impact Points


  • 1997–2015
    • Nottingham Trent University
      • School of Science and Technology
      Nottigham, England, United Kingdom
  • 1973–2008
    • The University of Sheffield
      • • Institute for Cancer Studies
      • • Medical School
      Sheffield, England, United Kingdom
  • 2007
    • University of Nottingham
      Nottigham, England, United Kingdom
  • 2003
    • University of Tuebingen
      • Department of Internal Medicine
      Tübingen, Baden-Wuerttemberg, Germany
  • 2001
    • University of Liverpool
      Liverpool, England, United Kingdom
  • 1995
    • Leidos Biomedical Research
      Maryland, United States