Metastatic neuroblastoma is one of the most challenging malignancies of childhood, being associated with the highest death rate in pediatric oncology (20%). Moreover its prognosis is very poor, practically incurable, what shows the inability of nowadays chemotherapy to eradicate all the illness, underlining the need for novel therapeutic approaches. A current study of the European Group for study of the Neuroblastoma has shown profits in the survival of patients by means of the combination of several drugs (protocol COJEC: vincristine, carboplatin, etoposide and ciclofosfamide). However, such treatment shows a very important deep medullary aplasia as a secondary effect. Our hypothesis is that encapsulation of the NB drug cocktail can significantly improve nowadays disease treatment in such: I) will protect drugs from degradation before reaching cancer cells, II) will ensure their simultaneous actuation and III) last but not least, it will allow us to minimize undesirable medullary aplasia side effects upon specific vectorization of the drug cocktail to the target cells with targeting agents able to address GD2, a glycolipid highly expressed on the cell surface of neuroblastoma. Such exigent specifications require a unique multifunctional system that not all the reported drug carriers can achieve. Our choice is a new family of coordination polymer (CP) nanoparticles rrecently used with this aim by the host group due to their advantages: I) can encapsulate multiple active principles with high yield within the same particle, II) the presence of biocompatible metal ions can add additional fluorescence properties that allow us to follow the cell internalization and biodistribution, III) nanoparticles can be functionalized with specific targeting biomolecules and IV) preliminary in vitro cytotoxicity assays already showed that the encapsulated drugs could be effectively used to induce the cell death.

Glioblastoma multiforme (GBM) is both the most common and lethal primary malignant brain tumor. In the last century we have accumulated tremendous amounts of data on this type of cancer, but we have achieved very little improvement in its treatment. Despite decades of concerted effort and advances in surgery, radiation and chemotherapy, the median survival is 15 months. The inadequate progress in treatment led us to reexamine the gliomagenesis theory and reconsider the cell of origin of this deadly disease. We recently developed a mouse glioma model using Cre-inducible lentiviral vectors that faithfully recapitulate the pathophysiology of human glioblastomas. Using this model, our results suggested that most differentiated cells in the central nervous system (CNS) upon defined genetic alterations undergo reprogramming to generate a neural stem cell (NSC) or progenitor state to initiate and maintain the tumor progression, as well as to give rise to the heterogeneous populations observed in malignant gliomas. We also reported the transdifferentiation of tumor cells to form tumor derived endothelial cells (TDEC) to generate new tumor blood vessels. I propose a multidisciplinary approach to investigate the mechanisms of tumor cell reprogramming and the potential development of novel therapeutic modalities. I will combine molecular biology, cancer biology, immunology, biochemistry and nanotechnology to address these lines of investigation both in vitro and in vivo in a novel mouse model of GBM.

Most cancers remain 'incurable' and life-thretening. Cancer stem cells (CSCs) are the source of chemo/radioresistance and responsible for cancer recurrence which suggests the urgent requirement of CSC-targeting drugs. Drug development is a slow (15 years/drug) and costly (US$1.5bn/drug) procedure with only 5-25% of new oncology drugs in clinical development actually reaching the market mainly due to the toxicity of novel molecules. This dilemma has led to an increasing appreciation of the potential of repurposing of known drugs. We have demonstrated that Disulfiram (DS), an old anti-alcoholism drug, possesses excellent anti-CSC activity with low toxicity to normal cells. Whereas its cancer clinial indication is limited by its bio-instability (~4 min half-life in blood stream). Our pilot data demonstrated that the anticancer efficacy of DS is significantly improved when mild extending its half-life by liposome encapsulation. In this study, the Incoming Fellow, who has very strong technical knowhow in cancer research, molecular pharmacology, anticancer drug development and nano-encapsulation, will bring novel nano-biomaterials invented in China into Europe. Taking advantage of the state-of-the-art facilities, CSC models, pharmaceutical resarch and developmental expertise and scientific/technical support from the Incoming Host and the other European collaborators, we will develop a long-circulating nano-encapsulated DS. The anticancer activity of the nano-encapsulated DS will be examined in vitro and in vivo in breast and liver cancer cell lines as well as the relevant CSC models. This study will pave the path for clinical trial of DS in cancer indication. The significance of this project will be: 1. Expand and extend our FP7-IRSES (2011-16) platform to strenthen long-term collaboration between China and EU partners; 2. Develop a new cancer therapeutics for the benefic of healthcare in Europe; 3. Open a new drug developmental window to benefit European economy.

The past decade has seen substantial advances in our understanding of cancer molecular biology and the technologies available to study it, emphasising the importance of the molecular mechanisms of carcinogenesis in cancer research. We now face having to therapeutically aim for many less common targets rather than a few all-cancer present targets. Effective single molecular targets therapies are generally not sufficient to elicit durable clinical responses and the development of drug resistance is an increasing problem. Consideration of only a single drug–target interaction in vivo has proven to be overly simplistic. The ultimate goal of this proposal is to generate metallodrugs whose mechanism of action is understood and whose targets are identified. These multitargeting drugs would be a more realistic option by leading rational co-extinction strategies for specific cancers. Current cross-discipline trainings make possible the alliance of inorganic chemistry with cell and molecular biology. The unprecedented potential for design of metallodrugs has not been overseen and medicinal bioinorganic chemistry is rapidly expanding. This interdisciplinary proposal involves chemistry, biology and physics, with potential not only for the discovery of novel medicines for cancer treatment, but also for the development of new methodologies to modulate and deconvolute the technology behind the tumour cell machinery. By uncovering the operating principles and mechanisms of action of our metallodrugs at the nanoscale (i.e. subcellular level) we aim to inform on what biological context its destruction would lead to cell death and also to tumour regression. These metallo-medicines will exploit the extraordinary features of transition metal complexes, in particular the capability for in tumour activation, and the possibility of being loaded into nanocarriers, conferring control on the drug reactivity, and thus minimising undesired side effects, often responsible for drug failure.

The project is aimed at investigation of the novel routes to prepare functional 2D-substrates or 3D-scaffolds with artificial cell-instructive niches for cardiovascular and bone implants using sophisticated plasma- and electron beam-assisted nanofabrication technologies. The project's grand challenges are as follows: 1) Plasma-assisted fabrication of two-dimensional (2D) substrates and three-dimensional (3D) scaffolds of polymers, titanium and shape-memory alloys to control the differentiation of MSCs towards osteogenic and vascular (endothelial) lineages 2) Deterministic nanofabrication of the endothelial cell-targeted surface chemistry, topography and charge of two-dimensional (2D) substrates and three-dimensional (3D) scaffolds for the prevention of thrombosis of polymers, titanium and shape-memory alloys-based materials 3) Control over the hydrophobic nitric oxide groups containing surface chemistry, wettability and charge that prevent the formation of biofilm and adhesion of platelets 4) Differential diagnostics of cell associations and bioengineering constructions in vitro by use of synchrotron radiation 5) The development and studying of the novel 2D-substrates and 3D polymer scaffolds and their behavior in a bio-reactor (via tissue engineering) in vitro by use of dedicated X-ray multiple contrast diagnostics (objective for re-integration phase of the project). Completing the research planned during the PlasmaNanoSmart project it is suggested to obtain new fundamental data on biological response of novel elaborated biocomposites, which will serve further breakthrough in the field of 3D-bioscaffold technologies for regenerative medicine. The 'cell biochips' advanced technology for 'smart implants' carrying artificial niches for MSCs will be developed which allows us to gradually replace bioinert and bioactive materials. This new bioengineering (biomimetical) approach will reduce the medical, social and economic risks for the public (compared to cell therapy).

The use of Acellular Technology to stimulate the body's own repair processing is an emerging direction in regenerative medicine, which may tackle one of challenges in orthopedic treatment where how to treat bone loss or bone fracture due to osteoporosis is unsolved. The main objective of this project is to biofabricate new bioinspired scaffolds enabling off-shelf, scalable and stimulating multiple cellular actions including stem cell infiltration/adhesion; differentiation of osteoblast and endothethial cells for treatment of bone defects. The proposal will develop new multifaceted 3D composite scaffolds combined the advantages of electrospun nanofibers, porous foam and active chemicals conjugation enabling to provide biological, physical and mechanical properties for mesenchymal stem cells adhesion, migration, and differentiation and angiogenesis. The proposal will also develop an in vitro dynamic culture model mimicking bone development in vivo to evaluate the efficiency of scaffolds in order to reduce the use of animal models. The project proposes to bring an outstanding young researcher, Dr Lü, who was trained in the State Key Laboratory of Bioelectronics in Southeast University, the top 20 university in China, to undertake such multidisciplinary research project with host institution in Keele University, UK. Dr Lü has worked in biofabrcation field in past 5 years, and have established excellent track record in smart nanofiber fabrication and applications. The fellow's experience and knowledge will be effectively transferred to host group and other European research groups through the delivering the targets of the project and disseminating of her previous research outcomes by seminar, joint publication and visiting other laboratories. The fellowship will also aim to build collaboration with third country through Dr Lü's research links in China after the fellowship, which will enhance European knowledge-based economy in general and healthcare in specifically.

Viruses and bacteria utilize proteins to attach and infect cells and tissues. Viruses have envoloped proteins that especifically recongnize receptors in the surface of the target cells. HIV-1 recognices receptor CD4 in the surface of T cell throghout its envolope glycoprotein gp120. In the case of bacteria, they attach to tissues using long filament called pilus. Bacterial pilus type 1 is composed of several protein subunit arranged in chain, FimA-FimG-FimG-FimH. The more external domain, FimH, is the adhesin binding domain that establishes the mechanical anchoring to tissues. Both, bacterial and viral proteins withstand mechanical forces than can go from few piconewtons to hundreds. However, very little is known about how force modify the structure and features of these proteins and ultimately how its affects infection. In this project we aim to investigate the effect of mechanical forces in the anchoring proteins and its role during attachment. We will concentrate in viral receptors CD4 and bacterial fimbriae proteins (Fim). We will use a novel atomic force spectometer that allows us to apply calibrated forces to a single protein molecule. This technique allows also monitoring chemical reaction under force such as the reduction of disulfide bonds or the binding of peptides and antibodies. These processes are known to be implicated in the infection of viruses and bacteria and they may have a mechanical origin. We will use bioinformatics and high-throughout screening techniques to identify molecules that alter the nanomecanichs of these anchoring proteins and that can potentially be used to prevent infections.

Nanotechnology is expected to have a big impact on most of our life. Nanostructred materials become more and more important in various fields such as nanoelectronics, information storage technology etc. At the nanometer scale, i.e. 1-100 nm, material properties are clearly size dependent and new properties are expected. Among functional materials nanoscale ferroelectrics can have a major role because they can be applied in different fields such as sensors, actuators, memory devices and optics. However they cannot be applied to nanometer scale devices before the influence of the lateral size on physical properties will be clarified.In order to find answer for the problems there is a need to have good quality nanoscale structures. It is a challenge to fabricate such structures in this range using both lithography (¿top¿down¿ approach) and self-assembling and self-patterning methods (¿bottom¿up¿ approach). Whereas conventional lithographic systems work usually with a resolution of about 100 nm the bottom-up approaches allow the inexpensive fabrication of structures with size of 10-20 nm. The main goal of the work is preparation of nanosized ferroelectric crystals by self-assembling methods. Successful strategies and routes have been developed to synthesize nanoscale materials of numerous simple systems such as semiconductors or metals. Complex systems such as ferroelectric oxides are not yet systematically addressed, despite of the possibility of discovering new materials with unique properties. Physical route based on the concept of microstructural instability of ultrathin films and chemical routes will be applied to obtain different perovskite crystals. A good quality of nanostructures that lateral dimension can be tuned in nanometer range is expected to fabricate and in future this will allow investigating structure-property relations (e.g. by transmission electron microscopy and piezoresponse force microscopy) and solve ¿size effects¿ problem.

This proposal aims to improve the current generation of organic photovoltaic materials by controlling the molecular morphology, a key parameter in the development of organic solar cells. Self-organisation is activated by a newly discovered nanophase segregation process between rod- and disc-shaped molecules. Moreover, the overall liquid crystalline properties of the system allow macroscopic alignment, giving rise to an optimised geometry at all length scales. The proposed project covers the entire chain of knowledge: the design and preparation of the nanophase segregating materials, a detailed investigation of the electro-optical properties, and the analysis of the photovoltaic behaviour. This approach is an attractive method for studying functional materials and allows a direct link from fundamental research to technology-based industries. Apart from developing new concepts in light harvesting and sustainable energies, the proposal envisages advances in the field of nanosciences, particularly in the control of self-organisation and nanostructure formation. Basic understanding of the parameters for self-organisation will be generated, which contributes to the process of conceptualisation, required to support future technological breakthroughs in the field of nanosciences. In the proposal, a close collaboration between the scientist from top-level institutes like MIT, Boston and the University of Nijmegen is realised. The institutes provide a state-of-the-art training opportunity for the applicant. Knowledge and experience built-up during the project can easily disseminate into national and European projects concerning photovoltaic technologies.

This project aims to combine two recent breakthroughs in solution-processed thin-film solar photovoltaics (PVs) to demonstrate a low-cost, stable PV device with an efficiency approaching conventional crystalline silicon devices. The aim will be achieved by integrating singlet fission, a process capable of pushing PV efficiencies beyond conventional limits, with recent exciting perovskite results. The researcher is uniquely suited to this ambitious project, which will engage him with world-leading techniques, collaborations, and transferrable skills and help him to achieve his goal of establishing a leading UK-based device spectroscopy research group. The project comprises an outgoing phase in Prof. Valdimir Bulovic's Organic & Nanostructured Electronics Group at the Massachusetts Institute of Technology, where their unrivalled expertise in the deposition and nanopatterning of materials will be applied to perovskite/singlet fission devices. This expertise will be transferred back to Prof. Sir Richard Friend's Optoelectronics (OE) Group at Cambridge University, world-leaders in ultrafast spectroscopy. Device behaviour will be elucidated and performance optimised by studying ultrafast phenomena such as the dynamics and mechanism of charge generation. Such a partnership of high-end nanoengineering and ultrafast spectroscopy is yet to be achieved and is likely to lead to revolutionary breakthroughs. The work will ensure that state-of-the-art expertise not currently available in the European Research Area (ERA) is transferred to the European community. This will create strong international links between the two leading groups, with enormous potential for intellectual property generation and industry involvement through OE Group spin-outs and partners and knowledge transfer from interaction with successful enterprises in the Boston area. This will increase Europe's competitiveness in the solar energy sector and ensure its energy security and emission targets are reached.