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Johdi N.A.,Imperial College London | Johdi N.A.,UKM Medical Molecular Biology Institute UMBI | Harman R.,Imperial College London | Sanjuan I.,Imperial College London | And 5 more authors.
Protein Expression and Purification | Year: 2013

Tumour-associated splice variants of fibronectin are a major source of tumour-matrix associated targets and are proving very successful in the development of clinical agents to treat cancer. One of the first monoclonal antibodies to be produced to this target, murine BC-1, recognises a cryptic epitope in domain 7 of the B-form splice variant (EDB-FN). Antibody fragments based on this immunoglobulin (IgG) were unstable, but BC-1 humanisation provided an opportunity to produce a more stable single-chain Fv (scFv). The variable domains of the humanized BC-1 IgG were sub-cloned and constructed into a scFv (HuBC-1 scFv) which was successfully expressed in Escherichia coli. The scFv retained its conformationally-sensitive epitope recognition and demonstrated a good affinity to the target of around 50 nM as measured by ELISA, Surface Plasmon Resonance and Flow Cytometry. Furthermore, the scFv was thermostable and stable in serum allowing substantial localisation to human tumours grown in mouse xenograft models. This scFv could form the basis of future tumour-specific biopharmaceuticals.© 2013 Georg Thieme Verlag KGStuttgart . New York. Source


Prokopi M.,Trojantec Ltd | Prokopi M.,Cyprus University of Technology | Kousparou C.A.,Trojantec Ltd | Epenetos A.A.,Trojantec Ltd | Epenetos A.A.,St. Bartholomews Hospital
Frontiers in Oncology | Year: 2014

MicroRNAs (miRNAs) have been implicated in the development of some if not all cancer types and have been identified as attractive targets for prognosis, diagnosis and therapy of the disease. MiRNAs are a class of small non-coding RNAs (20-22 nucleotides in length) that bind imperfectly to the 3'-untranslated region of target mRNA regulating gene expression. Aberrantly expressed miRNAs in cancer, sometimes known as oncomiRNAs, have been shown to play a major role in oncogenesis, metastasis and drug resistance. Amplification of oncomiRNAs during cancer development correlates with the silencing of tumor suppressor genes; on the other hand, down-regulation of miRNAs has also been observed in cancer and cancer stem cells (CSCs). In both cases, miRNA regulation is inversely correlated with cancer progression. Growing evidence indicates that miRNAs are also involved in the metastatic process by either suppressing or promoting metastasis-related genes leading to the reduction or activation of cancer cell migration and invasion processes. In particular, circulating miRNAs (vesicle-encapsulated or non-encapsulated) have significant effects on tumorigenesis: membrane-particles, apoptotic bodies and exosomes have been described as providers of a cell-to-cell communication system transporting oncogenic miRNAs from tumors to neighboring cells and distant metastatic sites. It is hypothesized that miRNAs control cancer development in a traditional manner, by regulating signaling pathways and factors. In addition, recent developments indicate a non-conventional mechanism of cancer regulation by stem cell reprogramming via a regulatory network consisting of miRNAs and Wnt/β-catenin, Notch, and Hedgehog signaling pathways, all of which are involved in controlling stem cell functions of CSCs. In this review, we focus on the role of miRNAs in the Notch pathway and how they regulate CSC self-renewal, differentiation and tumorigenesis by direct/indirect targeting of the Notch pathway. © 2014 Prokopi, Kousparou and Epenetos. Source


Prokopi M.,Trojantec Ltd | Prokopi M.,Cyprus University of Technology | Kousparou C.A.,Trojantec Ltd | Epenetos A.A.,Trojantec Ltd | And 3 more authors.
Frontiers in Oncology | Year: 2015

MicroRNAs (miRNAs) have been implicated in the development of some if not all cancer types and have been identified as attractive targets for prognosis, diagnosis, and therapy of the disease. miRNAs are a class of small non-coding RNAs (20-22 nt in length) that bind imperfectly to the 3'-untranslated region of target mRNA regulating gene expression. Aberrantly expressed miRNAs in cancer, sometimes known as oncomiRNAs, have been shown to play a major role in oncogenesis, metastasis, and drug resistance. Amplification of oncomiRNAs during cancer development correlates with the silencing of tumor suppressor genes; on the other hand, down-regulation of miRNAs has also been observed in cancer and cancer stem cells (CSCs). In both cases, miRNA regulation is inversely correlated with cancer progression. Growing evidence indicates that miRNAs are also involved in the metastatic process by either suppressing or promoting metastasis-related genes leading to the reduction or activation of cancer cell migration and invasion processes. In particular, circulating miRNAs (vesicle-encapsulated or non-encapsulated) have significant effects on tumorigenesis: membrane-particles, apoptotic bodies, and exosomes have been described as providers of a cell-to-cell communication system transporting oncogenic miRNAs from tumors to neighboring cells and distant metastatic sites. It is hypothesized that miRNAs control cancer development in a traditional manner, by regulating signaling pathways and factors. In addition, recent developments indicate a non-conventional mechanism of cancer regulation by stem cell reprograming via a regulatory network consisting of miRNAs and Wnt/ß-catenin, Notch, and Hedgehog signaling pathways, all of which are involved in controlling stem cell functions of CSCs. In this review, we focus on the role of miRNAs in the Notch-pathway and how they regulate CSC self-renewal, differentiation and tumorigenesis by direct/indirect targeting of the Notch-pathway. © 2015 Prokopi, Kousparou and Epenetos. Source


Pitsillides C.,Cyprus University of Technology | Kapnisis K.,Cyprus University of Technology | Prokopi M.,Trojantec Ltd | Kousparou C.,Trojantec Ltd | Anayiotos A.,Cyprus University of Technology
IEEE 12th International Conference on BioInformatics and BioEngineering, BIBE 2012 | Year: 2012

We report a new approach for potential monitoring of tumor burden in experimental animals using multichannel in vivo flow cytometry, a novel optical technique that enables the realtime, continuous detection and quantification of fluorescently labeled cells in the circulation without the need for blood extraction. The ability to non-invasively track circulating cells in real time and in their native environment, opens up enormous possibilities for new investigations into the mechanisms that govern the complex trafficking and tissue interactions of these cells in a wide range of clinical and biological fields such as cancer, stem cell biology and immunology. We have developed the in vivo flow cytometer in order to track circulating cancer cells in a mouse model and provide a new, non-invasive method for the monitoring of cancer disease progression as well as the response to therapeutic intervention. © 2012 IEEE. Source


Kapnisis K.K.,Cyprus University of Technology | Pitsillides C.M.,Cyprus University of Technology | Prokopi M.S.,Trojantec Ltd | Lapathitis G.,Cyprus Institute of Neurology and Genetics | And 6 more authors.
Journal of Biomedical Materials Research - Part A | Year: 2016

The popularity of vascular stents continues to increase for a variety of applications, including coronary, lower limb, renal, carotid, and neurovascular disorders. However, their clinical effectiveness is hindered by numerous postdeployment complications, which may stimulate inflammatory and fibrotic reactions. The purpose of this study was to evaluate the vessel inflammatory response via in vivo imaging in a mouse stent implantation model. Corroded and noncorroded self-expanding miniature nitinol stents were implanted in mice abdominal aortas, and novel in vivo imaging techniques were used to assess trafficking and accumulation of fluorescent donor monocytes as well as cellular proliferation at the implantation site. Monocytes were quantitatively tracked in vivo and found to rapidly clear from circulation within hours after injection. Differences were found between the test groups with respect to the numbers of recruited monocytes and the intensity of the resulting fluorescent signal. Image analysis also revealed a subtle increase in matrix metalloproteinase activity in corroded compared with the normal stented aortas. In conclusion, this study has been successful in developing a murine stent inflammation model and applying novel in vivo imaging tools and methods to monitor the complex biological processes of the host vascular wall response. © 2015 Wiley Periodicals, Inc. Source

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