274 results found
Gorroño-Etxebarria I, Aguirre U, Sanchez S, et al., 2019, Wnt-11 as a potential prognostic biomarker and therapeutic target in colorectal cancer, Cancers, Vol: 11, ISSN: 2072-6694
The expression of the secreted factor Wnt-11 is elevated in several types of cancer, includingcolorectal cancer, where it promotes cancer cell migration and invasion. Analysis of colorectalcancer gene expression databases associated WNT11 mRNA expression with increased likelihood ofmetastasis in a subset of patients. WNT11 expression was correlated with the expression of the Wntreceptors FZD6, RYK, and PTK7, and the combined expression of WNT11, FZD6 and RYK or PTK7was associated with an increased risk of 5-year mortality rates. Immunohistochemical analysis ofWnt-11 in a cohort of 357 colorectal cancer patients found significantly higher Wnt-11 levels in tumors,compared with benign tissue. Elevated Wnt-11 levels occurred more frequently in rectal tumors thanin colonic tumors and in tumors from women than men. In univariate analysis, increased Wnt-11expression was also associated with tumor invasion and increased 5-year mortality. High Wnt-11levels were not associated with high levels of nuclear β-catenin, suggesting Wnt-11 is not simplyan indicator for activation of β-catenin-dependent signaling. Expression of Wnt-11 in colorectalcancer cell lines expressing low endogenous Wnt-11 inhibited β-catenin/Tcf activity and increasedATF2-dependent transcriptional activity. WNT11 gene silencing and antibody-mediated inhibitionof Wnt-11 in colorectal cancer cell lines expressing high Wnt-11 reduced their capacity for invasion.Together, these observations suggest that Wnt-11 could be a potential target for the treatment ofpatients with invasive colorectal cancer.
Al-Shareef Z, Kardooni H, Murillo-Garzon V, et al., 2018, Protective effect of stromal Dickkopf-3 in prostate cancer: opposing roles for TGFBI and ECM-1, Oncogene, Vol: 37, Pages: 5305-5324, ISSN: 0950-9232
Aberrant transforming growth factor–β (TGF-β) signaling is a hallmark of the stromalmicroenvironment in cancer. Dickkopf-3 (Dkk-3), shown to inhibit TGF-β signaling, isdownregulated in prostate cancer and upregulated in the stroma in benign prostatichyperplasia, but the function of stromal Dkk-3 is unclear. Here we show that DKK3 silencingin WPMY-1 prostate stromal cells increases TGF-β signaling activity and that stromal cellconditionedmedia inhibit prostate cancer cell invasion in a Dkk-3-dependent manner. DKK3silencing increased the level of the cell-adhesion regulator TGF-β–induced protein (TGFBI)in stromal and epithelial cell-conditioned media, and recombinant TGFBI increased prostatecancer cell invasion. Reduced expression of Dkk-3 in patient tumors was associated withincreased expression of TGFBI. DKK3 silencing reduced the level of extracellular matrixprotein-1 (ECM-1) in prostate stromal cell-conditioned media but increased it in epithelialcell-conditioned media, and recombinant ECM-1 inhibited TGFBI-induced prostate cancercell invasion. Increased ECM1 and DKK3 mRNA expression in prostate tumors wasassociated with increased relapse-free survival. These observations are consistent with amodel in which the loss of Dkk-3 in prostate cancer leads to increased secretion of TGFBIand ECM-1, which have tumor-promoting and tumor-protective roles, respectively.Determining how the balance between the opposing roles of extracellular factors influencesprostate carcinogenesis will be key to developing therapies that target the tumormicroenvironment.
Kardooni H, Gonzalez-Gualda E, Stylianakis E, et al., 2018, CRISPR-mediated reactivation of DKK3 expression attenuates TGF-beta signaling in prostate cancer, Cancers, Vol: 10, ISSN: 2072-6694
The DKK3 gene encodes a secreted protein, Dkk-3, that inhibits prostate tumor growth and metastasis. DKK3 is downregulated by promoter methylation in many types of cancer, including prostate cancer. Gene silencing studies have shown that Dkk-3 maintains normal prostate epithelial cell homeostasis by limiting TGF-β/Smad signaling. While ectopic expression of Dkk-3 leads to prostate cancer cell apoptosis, it is unclear if Dkk-3 has a physiological role in cancer cells. Here, we show that treatment of PC3 prostate cancer cells with the DNA methyltransferase (DNMT) inhibitor decitabine demethylates the DKK3 promoter, induces DKK3 expression, and inhibits TGF-β/Smad-dependent transcriptional activity. Direct induction of DKK3 expression using CRISPR-dCas9-VPR also inhibited TGF-β/Smad-dependent transcription and attenuated PC3 cell migration and proliferation. These effects were not observed in C4-2B cells, which do not respond to TGF-β. TGF-β signals can regulate gene expression directly via SMAD proteins and indirectly by increasing DNMT expression, leading to promoter methylation. Analysis of genes downregulated by promoter methylation and predicted to be regulated by TGF-β found that DKK3 induction increased expression of PTGS2, which encodes cyclooxygenase-2. Together, these observations provide support for using CRISPR-mediated induction of DKK3 as a potential therapeutic approach for prostate cancer and highlight complexities in Dkk-3 regulation of TGF-β signaling.
Murillo-Garzón V, Gorroño-Etxebarria I, Åkerfelt M, et al., 2018, Frizzled-8 integrates Wnt-11 and transforming growth factor-β signaling in prostate cancer, Nature Communications, Vol: 9, ISSN: 2041-1723
Wnt-11 promotes cancer cell migration and invasion independently of β-catenin but the receptors involved remain unknown. Here, we provide evidence that FZD8 is a major Wnt-11 receptor in prostate cancer that integrates Wnt-11 and TGF-β signals to promote EMT. FZD8 mRNA is upregulated in multiple prostate cancer datasets and in metastatic cancer cell lines in vitro and in vivo. Analysis of patient samples reveals increased levels of FZD8 in cancer, correlating with Wnt-11. FZD8 co-localizes and co-immunoprecipitates with Wnt-11 and potentiates Wnt-11 activation of ATF2-dependent transcription. FZD8 silencing reduces prostate cancer cell migration, invasion, three-dimensional (3D) organotypic cell growth, expression of EMT-related genes, and TGF-β/Smad-dependent signaling. Mechanistically, FZD8 forms a TGF-β-regulated complex with TGF-β receptors that is mediated by the extracellular domains of FZD8 and TGFBR1. Targeting FZD8 may therefore inhibit aberrant activation of both Wnt and TGF-β signals in prostate cancer.
Sita-Lumsden AR, Sita-Lumsden AR, Leach D, et al., 2017, A circulating miRNA signature to better stratify prostate cancer patients at diagnosis, 19th National Congress of Medical Oncology, Publisher: OXFORD UNIV PRESS, ISSN: 0923-7534
Sita-Lumsden AR, Leach D, Zivi A, et al., 2017, A signature of miRNAs in the blood to help prognosticate prostate cancer at the time of diagnosis., 53rd Annual Clinical Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X
Sita-Lumsden AR, Leach D, Zivi A, et al., 2017, A circulating miRNA signature to help prognosticate at prostate cancer diagnosis., ASCO Genitourinary Cancers Symposium, Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X
Pardo OE, Munro CE, Castellano L, et al., 2016, miR-515-5p controls cancer cell migration through MARK4 regulation, EMBO Reports, Vol: 17, Pages: 570-584, ISSN: 1469-221X
Here we show that miR-515-5p inhibits cancer cell migration and metastasis. RNA-seqanalyses of both estrogen receptor-positive and negative breast cancer cells overexpressingmiR-515-5p reveals down-regulation of NRAS, FZD4, CDC42BPA, PIK3C2Band MARK4 mRNAs. We demonstrate that miR-515-5p inhibits MARK4 directly 3’UTRinteraction and that MARK4 knockdown mimics the effect of miR-515-5p on breast andlung cancer cell migration. MARK4 over-expression rescues the inhibitory effects of miR-515-5p, suggesting miR-515-5p mediates this process through MARK4 down-regulation.Furthermore, miR-515-5p expression is reduced in metastases compared to primarytumours derived from both in vivo xenografts and samples from patients with breastcancer. Conversely, miR-515-5p overexpression prevents tumour cell dissemination ina mouse metastatic model. Moreover, high miR-515-5p and low MARK4 expressioncorrelate with increased breast and lung cancer patients’ survival, respectively. Takentogether, these data demonstrate the importance of miR-515-5p/MARK4 regulation incell migration and metastasis across two common cancers.
Caley MP, King H, Shah N, et al., 2015, Tumor-associated Endo180 requires stromal-derived LOX to promote metastatic prostate cancer cell migration on human ECM surfaces, Clinical & Experimental Metastasis, Vol: 33, Pages: 151-165, ISSN: 1573-7276
The diverse composition and structure of extracellular matrix (ECM) interfaces encountered by tumor cells at secondary tissue sites can influence metastatic progression. Extensive in vitro and in vivo data has confirmed that metastasizing tumor cells can adopt different migratory modes in response to their microenvironment. Here we present a model that uses human stromal cell-derived matrices to demonstrate that plasticity in tumor cell movement is controlled by the tumor-associated collagen receptor Endo180 (CD280, CLEC13E, KIAA0709, MRC2, TEM9, uPARAP) and the crosslinking of collagen fibers by stromal-derived lysyl oxidase (LOX). Human osteoblast-derived and fibroblast-derived ECM supported a rounded ‘amoeboid-like’ mode of cell migration and enhanced Endo180 expression in three prostate cancer cell lines (PC3, VCaP, DU145). Genetic silencing of Endo180 reverted PC3 cells from their rounded mode of migration towards a bipolar ‘mesenchymal-like’ mode of migration and blocked their translocation on human fibroblast-derived and osteoblast-derived matrices. The concomitant decrease in PC3 cell migration and increase in Endo180 expression induced by stromal LOX inhibition indicates that the Endo180-dependent rounded mode of prostate cancer cell migration requires ECM crosslinking. In conclusion, this study introduces a realistic in vitro model for the study of metastatic prostate cancer cell plasticity and pinpoints the cooperation between tumor-associated Endo180 and the stiff microenvironment imposed by stromal-derived LOX as a potential target for limiting metastatic progression in prostate cancer.
Romero D, Al-Shareef Z, Gorrono-Etxebarria I, et al., 2015, Dickkopf-3 regulates prostate epithelial cell acinar morphogenesis and prostate cancer cell invasion by limiting TGF-β-dependent activation of matrix metalloproteases., Carcinogenesis, Vol: 37, Pages: 18-29, ISSN: 1460-2180
Dickkopf-3 (Dkk-3) is a secreted protein whose expression is downregulated in many typesof cancer. Endogenous Dkk-3 is required for formation of acini in 3D cultures of prostateepithelial cells, where it inhibits transforming growth factor (TGF)-β/Smad signaling. Here,we examined the effects of Dkk-3 on the expression and activity of matrix metalloproteases(MMPs), which mediate the effects of TGF-β on extracellular matrix disassembly duringtissue morphogenesis and promote invasion of tumor cells. Silencing of Dkk-3 in prostateepithelial cells resulted in increased expression and enzyme activity of MMP-2 and MMP-9.Inhibition of MMP-9 partially restored normal acinar morphogenesis in Dkk-3-silencedRWPE-1 prostate epithelial cells. In prostate cancer, Dkk-3 inhibited TGF-β-dependentmigration and invasion. Inhibition was mediated by the Dkk-3 C-terminal cysteine-richdomain (Cys2), which also inhibited TGF-β-induced expression of MMP9 and MMP13. Incontrast, Dkk-3, but not Cys2, increased formation of normal acini in Dkk-3-silenced prostateepithelial cells. These observations highlight a role for Dkk-3 in modulating TGF-β/MMPsignals in the prostate, and suggest that the Dkk-3 Cys2 domain can be used as a basis fortherapies that target the tumor promoting effects of TGF-β signaling in advanced prostatecancer.
Brooke GN, Gamble SC, Hough MA, et al., 2015, Antiandrogens act as selective androgen receptor modulators at the proteome Level in prostate cancer cells, Molecular & Cellular Proteomics, Vol: 14, Pages: 1201-1216, ISSN: 1535-9484
Current therapies for prostate cancer include antiandrogens, inhibitory ligands of the androgen receptor, which repress androgen-stimulated growth. These include the selective androgen receptor modulators cyproterone acetate and hydroxyflutamide and the complete antagonist bicalutamide. Their activity is partly dictated by the presence of androgen receptor mutations, which are commonly detected in patients who relapse while receiving antiandrogens, i.e. in castrate-resistant prostate cancer. To characterize the early proteomic response to these antiandrogens we used the LNCaP prostate cancer cell line, which harbors the androgen receptor mutation most commonly detected in castrate-resistant tumors (T877A), analyzing alterations in the proteome, and comparing these to the effect of these therapeutics upon androgen receptor activity and cell proliferation. The majority are regulated post-transcriptionally, possibly via nongenomic androgen receptor signaling. Differences detected between the exposure groups demonstrate subtle changes in the biological response to each specific ligand, suggesting a spectrum of agonistic and antagonistic effects dependent on the ligand used. Analysis of the crystal structures of the AR in the presence of cyproterone acetate, hydroxyflutamide, and DHT identified important differences in the orientation of key residues located in the AF-2 and BF-3 protein interaction surfaces. This further implies that although there is commonality in the growth responses between androgens and those antiandrogens that stimulate growth in the presence of a mutation, there may also be influential differences in the growth pathways stimulated by the different ligands. This therefore has implications for prostate cancer treatment because tumors may respond differently dependent upon which mutation is present and which ligand is activating growth, also for the design of selective androgen receptor modulators, which aim to elicit differential proteomic responses
Rodriguez-Teja M, Gronau JH, Breit C, et al., 2015, AGE-modified basement membrane cooperates with Endo180 to promote epithelial cell invasiveness and decrease prostate cancer survival, JOURNAL OF PATHOLOGY, Vol: 235, Pages: 581-592, ISSN: 0022-3417
Rodriguez-Teja M, Gronau JH, Minamidate A, et al., 2015, Survival Outcome and EMT Suppression Mediated by a Lectin Domain Interaction of Endo180 and CD147, MOLECULAR CANCER RESEARCH, Vol: 13, Pages: 538-547, ISSN: 1541-7786
Alshaker H, Wang Q, Frampton AE, et al., 2015, Sphingosine kinase 1 contributes to leptin-induced STAT3 phosphorylation through IL-6/gp130 transactivation in oestrogen receptor-negative breast cancer, BREAST CANCER RESEARCH AND TREATMENT, Vol: 149, Pages: 59-67, ISSN: 0167-6806
Alshaker H, Krell J, Frampton AE, et al., 2014, Leptin induces upregulation of sphingosine kinase 1 in oestrogen receptor-negative breast cancer via Src family kinase-mediated, janus kinase 2-independent pathway, Breast Cancer Research, Vol: 16, ISSN: 1465-542X
Introduction: Obesity is a known risk factor for breast cancer. Sphingosine kinase 1 (SK1) is an oncogenic lipidkinase that is overexpressed in breast tumours and linked with poor prognosis, however, its role in obesity-drivenbreast cancer was never elucidated.Methods: Human primary and secondary breast cancer tissues were analysed for SK1 and leptin receptorexpression using quantitative real-time polymerase chain reaction (qRT-PCR) assay. Leptin-induced signalling wasanalysed in human oestrogen receptor (ER)-positive and negative breast cancer cells using Western blotting,qRT-PCR and radiolabelling assays.Results: Our findings show for the first time that human primary breast tumours and associated lymph nodemetastases exhibit a strong correlation between SK1 and leptin receptor expression (Pearson R = 0.78 and R = 0.77,respectively, P <0.001). Both these genes are elevated in metastases of ER-negative patients and show a significantincrease in patients with higher body mass index (BMI). Leptin induces SK1 expression and activation in ER-negativebreast cancer cell lines MDAMB-231 and BT-549, but not in ER-positive cell lines. Pharmacological inhibition andgene knockdown showed that leptin-induced SK1 activity and expression are mediated by activation of extracellularsignal-regulated kinases 1/2 (ERK1/2) and Src family kinase (SFK) pathways, but not by the major pathwaysdownstream of leptin receptor (LEPR) - janus kinase 2 (JAK2) and signal transducer and activator of transcription 3(STAT3). Src-homology 2 domain-containing phosphatase 2 (SHP2) appeared to be key to SK1 activation, and mayfunction as an adaptor protein between SFKs and LEPR. Importantly, leptin-induced breast cancer cell proliferationwas abrogated by SK1-specific small interfering RNA (siRNA).Conclusions: Overall, our findings demonstrate a novel SFK/ERK1/2-mediated pathway that links leptin signallingand expression of oncogenic enzyme SK1 in breast tumours and suggest the potential significance
Campa VM, Baltziskueta E, Bengoa-Vergniory N, et al., 2014, A screen for transcription factor targets of Glycogen Synthase Kinase-3 highlights an inverse correlation of NFκB and Androgen Receptor Signaling in Prostate Cancer, ONCOTARGET, Vol: 5, Pages: 8173-8187
Brooke GN, Powell SM, Lavery DN, et al., 2014, Engineered repressors are potent inhibitors of androgen receptor activity, Oncotarget, Vol: 5, Pages: 959-969, ISSN: 1949-2553
Prostate cancer growth is dependent upon the Androgen Receptor (AR) pathway, hence therapies for this disease often target this signalling axis. Such therapies are successful in the majority of patients but invariably fail after a median of 2 years and tumours progress to a castrate resistant stage (CRPC). Much evidence exists to suggest that the AR remains key to CRPC growth and hence remains a valid therapeutic target. Here we describe a novel method to inhibit AR activity, consisting of an interaction motif, that binds to the AR ligand-binding domain, fused to repression domains. These ‘engineered repressors’ are potent inhibitors of AR activity and prostate cancer cell growth and importantly inhibit the AR under circumstances in which conventional therapies would be predicted to fail, such as AR mutation and altered cofactor levels.
Alshaker H, Alifrangis C, Mellor J, et al., 2014, Development of a new epigenetic-based blood test to stratify prostate cancer patients according to risk groups, INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, Vol: 34, Pages: S9-S9, ISSN: 1107-3756
Ottaviani S, Brooke GN, O'Hanlon-Brown C, et al., 2013, Characterisation of the androgen regulation of glycine <i>N</i>-methyltransferase in prostate cancer cells, JOURNAL OF MOLECULAR ENDOCRINOLOGY, Vol: 51, Pages: 301-312, ISSN: 0952-5041
Sita-Lumsden A, Fletcher CE, Dart DA, et al., 2013, Circulating nucleic acids as biomarkers of prostate cancer, BIOMARKERS IN MEDICINE, Vol: 7, Pages: 867-877, ISSN: 1752-0363
Pinho FG, Frampton AE, Nunes J, et al., 2013, Downregulation of microRNA-515-5p by the Estrogen Receptor Modulates Sphingosine Kinase 1 and Breast Cancer Cell Proliferation, CANCER RESEARCH, Vol: 73, Pages: 5936-5948, ISSN: 0008-5472
Krell J, Waxman J, 2013, Reforms in the English National Health Service: the voluntary sector in cancer care provision, LANCET ONCOLOGY, Vol: 14, Pages: 925-926, ISSN: 1470-2045
Dart DA, Waxman J, Aboagye EO, et al., 2013, Visualising Androgen Receptor Activity in Male and Female Mice, PLOS One, Vol: 8, ISSN: 1932-6203
Androgens, required for normal development and fertility of males and females, have vital roles in the reproductivetract, brain, cardiovascular system, smooth muscle and bone. Androgens function via the androgen receptor (AR), aligand-dependent transcription factor. To assay and localise AR activity in vivo we generated the transgenic “ARELuc”mouse, expressing a luciferase reporter gene under the control of activated endogenous AR. In vivo imaging ofandrogen-mediated luciferase activity revealed several strongly expressing tissues in the male mouse as expectedand also in certain female tissues. In males the testes, prostate, seminal vesicles and bone marrow all showed highAR activity. In females, strong activity was seen in the ovaries, uterus, omentum tissue and mammary glands. In bothsexes AR expression and activity was also found in salivary glands, the eye (and associated glands), adipose tissue,spleen and, notably, regions of the brain. Luciferase protein expression was found in the same cell layers asandrogen receptor expression. Additionally, mouse AR expression and activity correlated well with AR expression inhuman tissues. The anti-androgen bicalutamide reduced luciferase signal in all tissues. Our model demonstrates thatandrogens can act in these tissues directly via AR, rather than exclusively via androgen aromatisation to estrogensand activation of the estrogen receptor. Additionally, it visually demonstrates the fundamental importance of ARsignalling outside the normal role in the reproductive organs. This model represents an important tool forphysiological and developmental analysis of androgen signalling, and for characterization of known and novelandrogenic or antiandrogenic compounds.
Sita-Lumsden A, Dart DA, Waxman J, et al., 2013, Circulating microRNAs as potential new biomarkers for prostate cancer, British Journal of Cancer, Vol: 108, Pages: 1925-1930, ISSN: 1532-1827
Since they were first described in the 1990s, circulating microRNAs (miRNAs) have provided an active and rapidly evolving area of current research that has the potential to transform cancer diagnostics and therapeutics. In particular, miRNAs could provide potential new biomarkers for prostate cancer, the most common cause of cancer in UK men. Current diagnostic tests for prostate cancer have low specificity and poor sensitivity. Further, although many prostate cancers are so slow growing as not to pose a major risk to health, there is currently no test to distinguish between these and cancers that will become aggressive and life threatening. Circulating miRNAs are highly stable and are both detectable and quantifiable in a range of accessible bio fluids, thus have the potential to be useful diagnostic, prognostic and predictive biomarkers. This review aims to summarise the current understanding of circulating miRNAs in prostate cancer patients and their potential role as biomarkers.
Romero D, Kawano Y, Bengoa N, et al., 2013, Downregulation of Dickkopf-3 disrupts prostate acinar morphogenesis through TGF-β/Smad signalling, JOURNAL OF CELL SCIENCE, Vol: 126, Pages: 1858-1867, ISSN: 0021-9533
Kawano Y, Romero D, Bengora N, et al., 2013, LOSS OF DICKKOPF-3 EXPRESSION IMPAIRS PROSTATE ACINAR MORPHOGENESIS VIA ABERRANT TGF-β/SMAD SIGNALLING ACTIVATION, Annual Meeting of the American-Urological-Association (AUA), Publisher: ELSEVIER SCIENCE INC, Pages: E330-E330, ISSN: 0022-5347
Palmieri C, Caley MP, Purshouse K, et al., 2013, Endo180 modulation by bisphosphonates and diagnostic accuracy in metastatic breast cancer, BRITISH JOURNAL OF CANCER, Vol: 108, Pages: 163-169, ISSN: 0007-0920
Sturge J, Caley MP, Purshouse K, et al., 2012, The Collagen Receptor Endo180: A Metastatic Plasma Marker In Breast Cancer Modulated By Bisphosphonate Treatment, CANCER RESEARCH, Vol: 72, ISSN: 0008-5472
O'Hanlon Brown C, Waxman J, 2012, Current management of prostate cancer: dilemmas and trials., Br J Radiol, Vol: 85 Spec No 1, Pages: S28-S40
The past decade has witnessed significant advances in our understanding of the biology of prostate cancer. Androgen ablation/androgen receptor inhibition remains as the mainstay of treatment for advanced prostate cancer. Our understanding of the biology of prostate cancer has increased exponentially owing to advances in molecular biology. With this knowledge many intriguing issues have come to light, which clinicians and scientists alike strive to answer. These include why prostate cancer is so common, what drives the development of prostate cancer at a molecular level, why prostate cancer appears refractory to many families of cytotoxic chemotherapeutics, and why prostate cancer preferentially metastasizes to bone. Two clinical forms of prostate cancer have been identified: indolent organ confined disease, which elderly men often die of, and aggressive metastatic disease. A method of distinguishing between these two forms of the disease at an organ-confined stage remains elusive. Understanding the mechanisms of castrate resistance is a further issue of clinical importance. New trials of treatments, including molecular agents that target prostate cancer from a range of angles, have been instituted over the past 10-15 years. We can look at these trials not only as a chance to investigate the effectiveness of new treatments but also as an opportunity to further understand the complex biology of this disease.
Dart DA, Brooke GN, Sita-Lumsden A, et al., 2012, Reducing prohibitin increases histone acetylation, and promotes androgen independence in prostate tumours by increasing androgen receptor activation by adrenal androgens, ONCOGENE, Vol: 31, Pages: 4588-4598, ISSN: 0950-9232
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