Transcription factors controlling E-cadherin downregulation in ovarian cancer

This article has been accepted for publication in Bioscience Horizons. Published by Oxford University Press.© The Author(s) 2018. Transcription factors (TFs), such as Snail, Slug and Twist, control the down-regulation of cell-cell adhesion molecule Ecadherin in ovarian cancer. Low E-cadherin aids tumour cells in undergoing epithelial-mesenchymal transition (EMT) to motile morphology, disseminating to other organs. High TF levels have also correlated with chemoresistance and poor prognosis. This review aims to discern mechanisms of E-cadherin reduction by TFs and identifies hypoxia-inducible factor 1α (HIF1α) as an upstream regulator in hypoxic conditions. Association with chemoresistance is investigated, and whether its reversal is possible. Snail was found to bind more strongly to the E-cadherin promoter than Slug; it was suggested that Snail maintained EMT whilst Slug induced it. The use of differential zinc fingers by Snail and Slug to bind to the E-cadherin promoter supported this. HIF1α was shown to lie upstream of all three TFs and protein degradation or post-transcriptional regulation using miR-548c may regulate of Twist downstream. Further study into this is needed. High Snail expression correlated with cisplatin resistance, with knockdown of Snail reversing it. The same may be true for Twist and Slug, though some studies conflicted this. These findings show promising potential of TFs and HIF1α as therapeutic targets for EMT prevention and even chemoresistance reversal

Cathepsin D non-proteolytically induces proliferation and migration in human omental microvascular endothelial cells via activation of the ERK1/2 and PI3K/AKT pathways

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordEpithelial ovarian cancer (EOC) frequently metastasises to the omentum, a process that requires pro-angiogenic activation of human omental microvascular endothelial cells (HOMECs) by tumour-secreted factors. We have previously shown that ovarian cancer cells secrete a range of factors that induce pro-angiogenic responses e.g. migration, in HOMECs including the lysosomal protease cathepsin D (CathD). However, the cellular mechanism by which CathD induces these cellular responses is not understood. The aim of this study was to further examine the pro-angiogenic effects of CathD in HOMECs i.e. proliferation and migration, to investigate whether these effects are dependent on CathD catalytic activity and to delineate the intracellular signalling kinases activated by CathD. We report, for the first time, that CathD significantly increases HOMEC proliferation and migration via a non-proteolytic mechanism resulting in activation of ERK1/2 and AKT. These data suggest that EOC cancer secreted CathD acts as an extracellular ligand and may play an important pro-angiogenic, and thus pro-metastatic, role by activating the omental microvasculature during EOC metastasis to the omentum.FORCE Cancer Charit

Efficacy of systemic temozolomide-activated phage-targeted gene therapy in human glioblastoma.

Glioblastoma multiforme (GBM) is the most lethal primary intracranial malignant neoplasm in adults and most resistant to treatment. Integration of gene therapy and chemotherapy, chemovirotherapy, has the potential to improve treatment. We have introduced an intravenous bacteriophage (phage) vector for dual targeting of therapeutic genes to glioblastoma. It is a hybrid AAV/phage, AAVP, designed to deliver a recombinant adeno-associated virus genome (rAAV) by the capsid of M13 phage. In this vector, dual tumor targeting is first achieved by phage capsid display of the RGD4C ligand that binds the αvβ3 integrin receptor. Second, genes are expressed from a tumor-activated and temozolomide (TMZ)-induced promoter of the glucose-regulated protein, Grp78 Here, we investigated systemic combination therapy using TMZ and targeted suicide gene therapy by the RGD4C/AAVP-Grp78 Firstly, in vitro we showed that TMZ increases endogenous Grp78 gene expression and boosts transgene expression from the RGD4C/AAVP-Grp78 in human GBM cells. Next, RGD4C/AAVP-Grp78 targets intracranial tumors in mice following intravenous administration. Finally, combination of TMZ and RGD4C/AAVP-Grp78 targeted gene therapy exerts a synergistic effect to suppress growth of orthotopic glioblastoma.. This study was supported by a grant G0701159 of the UK Medical Research Council (MRC) and the Brain Tumour Research Campaign (BTRC). Keittisak Suwan is funded by the Children with Cancer UK (13/147 and 16/230). AMC is funded by ISCIII-FEDER (CP13/00189). JP received a stipend from the BTRC. EOA acknowledges support from Imperial College NIHR Biomedical Research Centre award (WSCC_P62585), Cancer Research UK grant (C2536/A16584), Medical Research Council grant (MC-A652- 5PY80), and Experimental Cancer Medicine Centres grant (C37/A7283)

Bacteriophage-Derived Vectors for Targeted Cancer Gene Therapy

Cancer gene therapy expanded and reached its pinnacle in research in the last decade. Both viral and non - viral vectors have entered clinical trials , and significant successes have been achieved. However, a systemic administration of a vector , illustrating safe, efficient , and targeted gene delivery to solid tumors has proven to be a major challenge. In this review, we summarize the current progress and challenges in the targeted gene therapy of cancer. Moreover, we highlight the recent developments of bacteriophage - derived vectors and their contributions in targeting cancer with therapeutic genes following systemic administration

Transcription factors controlling E-cadherin down-regulation in ovarian cancer

Transcription factors (TFs), such as Snail, Slug and Twist, control the down-regulation of cell–cell adhesion molecule E-cadherin in ovarian cancer. Low E-cadherin aids tumour cells in undergoing epithelial–mesenchymal transition (EMT) to motile morphology, disseminating to other organs. High TF levels have also correlated with chemoresistance and poor prognosis. This review aims to discern mechanisms of E-cadherin reduction by TFs and identifies hypoxia-inducible factor 1α (HIF1α) as an upstream regulator in hypoxic conditions. Association with chemoresistance is investigated, and whether its reversal is possible. Snail was found to bind more strongly to the E-cadherin promoter than Slug; it was suggested that Snail maintained EMT whilst Slug induced it. The use of differential zinc fingers by Snail and Slug to bind to the E-cadherin promoter supported this. HIF1α was shown to lie upstream of all three TFs and protein degradation or post-transcriptional regulation using miR-548c may regulate of Twist downstream. Further study into this is needed. High Snail expression correlated with cisplatin resistance, with knockdown of Snail reversing it. The same may be true for Twist and Slug, though some studies conflicted this. These findings show promising potential of TFs and HIF1α as therapeutic targets for EMT prevention and even chemoresistance reversal

Az ASS Berendezési Rendszerek Ipari Bt. vagyoni, pénzügyi és jövedelemi helyzetének elemzése

This is the final version. Available from Dove Medical Press via the DOI in this record.Background: Protein–graphene interactions have the potential to play a pivotal role in the future directions of nanomedicine. These interactions lead to diverse processes such as genera-tion of protein coronas, nano–bio interfaces, particle wrapping, and biocatalytic processes that could determine the ultimate fate of graphene nanocomposites in biologic systems. However, such interactions and their effects on the bioavailability of graphene have not yet been widely appreciated, despite the fact that this is the primary surface in contact with cells. Methods: This paper reports on the integrative physiochemical interaction between trypsin and graphene quantum dots (GQDs) to determine their potential biologic identity in enzyme engineering. This interaction was measured by a wide range of analytical methods. Results: Definitive binding and modulation of trypsin–GQDs was demonstrated for the first time by use of vibrational spectroscopy and wetting transparency, which revealed that trypsin was absorbed on GQDs’ surface through its cationic and hydrophilic residues. Our findings suggested that trypsin’s active sites were stabilized and protected by the GQDs, which were likely to be responsible for the high bioavailability of GQDs in enzymes. Conclusion: Our work demonstrates the efficacy of GQDs as an enzyme modulator with high specificity, and their great application potential in enzyme engineering as well as enzyme-based therapies.EPSRCFORCE Cancer Charit

Influence of luminescent graphene quantum dots on trypsin activity

Tanveer A Tabish,1,2 Md Zahidul I Pranjol,2 Ilayda Karadag,1 David W Horsell,1 Jacqueline L Whatmore,2 Shaowei Zhang1 1College of Engineering, Mathematics and Physical Sciences, University of Exeter, Exeter, UK; 2Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK Background: Protein–graphene interactions have the potential to play a pivotal role in the future directions of nanomedicine. These interactions lead to diverse processes such as generation of protein coronas, nano–bio interfaces, particle wrapping, and biocatalytic processes that could determine the ultimate fate of graphene nanocomposites in biologic systems. However, such interactions and their effects on the bioavailability of graphene have not yet been widely appreciated, despite the fact that this is the primary surface in contact with cells.Methods: This paper reports on the integrative physiochemical interaction between trypsin and graphene quantum dots (GQDs) to determine their potential biologic identity in enzyme engineering. This interaction was measured by a wide range of analytical methods.Results: Definitive binding and modulation of trypsin–GQDs was demonstrated for the first time by use of vibrational spectroscopy and wetting transparency, which revealed that trypsin was absorbed on GQDs’ surface through its cationic and hydrophilic residues. Our findings suggested that trypsin’s active sites were stabilized and protected by the GQDs, which were likely to be responsible for the high bioavailability of GQDs in enzymes.Conclusion: Our work demonstrates the efficacy of GQDs as an enzyme modulator with high specificity, and their great application potential in enzyme engineering as well as enzyme-based therapies. Keywords: graphene, enzyme, luminescence, bioavailability, surface energy&nbsp

In vitrotoxic effects of reduced graphene oxide nanosheets on lung cancer cells

journal_title: Nanotechnology article_type: paper article_title: toxic effects of reduced graphene oxide nanosheets on lung cancer cells copyright_information: © 2017 IOP Publishing Ltd date_received: 2017-08-30 date_accepted: 2017-10-24 date_epub: 2017-11-2

RADIUS Authentication in wireless lab environment

The aim of the thesis was to learn and research the development of the Wi-Fi access control methods. This topic will be covered in a chronological order starting from old open-access networks ending to modern methods used today. The practical aim of the study is to implement network access control with an external RADIUS server and to create a RADIUS lab for students. This method has two main advantages. The use of the external server provides a possibility to use one database for many devices like access points and routers. Resources used for this thesis are MB316 classroom access points, hubs, computers and virtual machines of Mikkeli University of Applied Sciences. In the beginning of the study, the theoretical foundation for the study is created with a literature review on authentication, authorization and accounting in Wireless Local Area Networks (WLANs). In the practical part of the study, I implement three different forms of wireless centralized authentication. These forms were autonomous access point RADIUS, Medium business RADIUS setup in Windows server environment and Enterprise RADIUS setup in Windows server environment The findings of the study suggest that autonomous access point solution is no longer a valid method even in small environments because it is not supported in Windows 10 operating system. The server-based solutions either implemented with one or multiple servers are the best for centralized user au-thentication management and access control