In partnership with Parco Tecnologico Padano SRL, Laboratorio di Ricerche Locorotondo of Dr. Nicola Locorotondo SRL, University of Catania, and Dr. AITA & Associated Inspectors Italia SRL.

Goal of the project: Design and create a molecular diagnostic panel on a real-time PCR platform and microfluidic cards, identify pathogens responsible for infectious diseases in immunosuppressed patients and transplantation, and new miRNA biomarkers associated with the reactivation and neoplastic transformation caused by viral agents, specific targets for opportunistic bacterial pathogens (staphylococci, viridans streptococci, and enterococci) and selected markers of antibiotic resistance.

In clinical scenarios associated with the onset of immunosuppression or immunodepression conditions, it is necessary to have access to appropriate standardized quantitative methods to monitor viral loads, identify cut-off levels to distinguish instances of reactivation, cut-off levels for therapeutic intervention, and monitor virology response to antiviral drug treatment.

This project has two specific goals:

1. develop a diagnostic panel for identification, quantification, and monitoring of viral and bacterial pathogens representing risk factors in the transplanted recipient, adopting methods that best suit the latter’s clinical monitoring requirements;
2. identify new markers and profiles associated with the reactivation and viral pathogenetic mechanisms that can represent a second-level diagnostic panel associated with the virology monitoring.

In order to reach these objectives a panel will be developed based on the following key features:

• Quality-quantity determination of the main bacterial and viral pathogens associated with infections in immunodepressed patients using real-time PCR.
• Format of sample on polymeric card structured on 96/384 test microfluidic modules.
• Standardization on patients in relevant clinical areas (patients undergoing organ and bone marrow transplantation).
• Definition of clinical cut-off for the different clinical areas.

At the same time, the possibility will be assessed to identify as potential accessory markers miRNAs associated with mechanisms of infection, latency, modulation, and viral reactivation, neoplastic transformation. Over the last ten years, it has been widely documented how the mechanisms of regulation determined by small non-coding RNAs are a generalized element of gene regulation, involved in the determinism of the entire genetic network that leads the modulation of the fundamental cellular processes. It has also been highlighted that, in addition to the miRNAs expressed by the cellular genome, there are also miRNAs encoded and expressed directly by the viral genome that establish complex relations of modulation and regulation of the host cell genes. One of the most studied models is the herpes viruses in which it has been demonstrated that there are specific viral miRNAs that control the mechanisms of viral latency, evasion of host immune system, etc. At a similar level, research can represent a new diagnostic horizon in the definition of new markers.

The project provides for the identification of target miRNAs to study their diagnostic use alongside a set of standard procedures for direct quantification of the viral genome. The miRNAs identified as potential candidates during the research will be transferred to the diagnostic platform developed for the panel’s viral targets as a second-level diagnostic panel associated with the viral panel.

The project’s research activity moves along two parallel lines which, although independent in terms of reachable results, do however have strong elements in common, particularly with regard to the innovative technology solutions utilized. The research will be conducted by the University of Catania (more involved in infectivology activities) and Ri.MED Foundation (oncology tasks). The outcomes will be shared and implemented with Biodiversity, accountable for the methodology tasks of experimental development, and with Dr. AITA, involved in more analytical tasks. Biodiversity and AITA will also provide feedback to research partners for the purpose of activating new activities or redesigning the existing ones, while Locorotondo Srl will have a strategic role in defining the characteristics of the final (marketable) product of research, such as sensitivity, specificity, reproducibility, and accuracy.

The main goals of this project are to develop an integrated methodological approach able to assess selected expressions of miRNAs and combine outcomes with those of conventional diagnostic (biochemical, histopathological, etc.) procedures in order to obtain an individual genetic “signature” to develop and/or implement new measures for diagnosis, prognostic classification, and customized treatment of the main human neoplastic diseases (breast, prostate, colorectal, and lung cancer).
This approach could lead to designing devices (biochips) divided by population and disease-specific that could later be validated thanks to their use on a series of biological samples (biobanks of peripheral blood, tissues), both non-tumoral and neoplastic, obtained inside controlled and randomized clinical trials, either ended or in progress. Data would then be analyzed using original and innovative mathematical models and bioinformatic tools allowing to obtain an optimal statistical capacity with as little data as possible. The biochips would subsequently be patented and marketed to be introduced in clinical practice for predictive, diagnostic, prognostic, and therapeutic purposes.
The main issues that will need to be addressed to achieve the set objectives basically concern two important aspects: the application of the utilized technology and the analysis of the data obtained. The individual and, most of all, population variability calls for a careful stratification of the study population and for a close assessment of potential confounding variables that could adversely affect the outcomes. Also, the current data analysis methods are still not fully adequate to their vastness and complexity.
This project would allow to overcome these issues primarily thanks to the use of banks of biological materials previously obtained by randomized clinical trials where potential confounding variables can easily be controlled, measured, and taken into consideration upon data analysis. In addition, the foreseen introduction of alternative mathematical models and systems and/or a different implementation of the currently existing bioinformatics tools, and also the use of third-generation sequencing technologies, should ensure a by far superior statistical significance and reliability of the data obtained, a significant reduction of times and costs and, therefore, a marked increase in the quality and competitiveness of the product (biochip).

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Approved in the scope of the PO FESR Sicily 2007-2013 – Line of Intervention 4.1.1.1.
October 2011 – April 2014

The SIASOPs project was sponsored by a partnership between SAN RAFFAELE (Rome), L.C. LABORATORI CAMPISI (Catania), UPMC (Palermo), ONTARIO (Catania) and by Ri.MED Foundation (Palermo) and CNRB (Roma).

Project proposal and impact
The project’s aim is to create a multi-institutional reference network in Sicily that will allow to create and organize a network of biobanks in the regional community. These biobanks will stem from the existing infrastructures and upgrade them guaranteeing the synergy and integration of individual resources for research infrastructures, in order to preserve tissue samples, tumor cells, DNA and other biological material that feed biomedical research, pharmaceutical companies’ research and diagnostics, and the activity of research centers and hospitals.

Motivations behind the project
The motivations that brought to the design of SIASOPs BioBank stem from the increased request of studies on biomedical and industrial translational and application research, based on the assessment of biological samples homogeneous for disease, clinical characteristics and sampling and storing processes. With all their information background, biology samples are increasingly requested to develop new and more effective research, products and medications, modern tools for traceability and logistics, new diagnosis. In order to create a biobank it is necessary to collect, manipulate and preserve samples in an appropriate manner and have a clinical documentation also from a technical point of view (IT support). The main goal of the project is to define an internal organizational model in the facilities able to guarantee a reliable traceability of the sample and also clinical and history information, using innovative electronic processes and systems, and also the aspects related to the definition and automation of the technical processes (specimen registration and preservation) and those related to filing clinical and history data. The value of a similar tracking system in the processes of the biobanks is hard to overestimate.

Technological goals of the project
The SIASOPs BioBank project has multiple goals: re-establish and re-assess the national and international standards of biobanks; develop and consolidate expertise on guidelines, ethical and legal regulations on the use of human biological materials for patient care and research applications; create a model for a new system to preserve, file and process samples for optimization and traceability of the procedures; define the joint pre-analytical processes to standardize the sampling and preservation of biology specimens and identify a group of bioindicators to be used in defining their quality criteria; design new software platforms to trace the life of the sample and define its characteristics. The strategic vision of SIASOPs BioBank is to provide technological tools for biobank governance able to regulate and coordinate the heterogeneous feeding of experimental materials with certified and shared acquisition protocols. Extending the network towards other clinical facilities means to set the boundaries of post-genomics (open doors to research, diagnostics, therapy and daily clinical practice).

Potential impact
The “Guidelines for the definition of a strategy to bioinformatics development in Italy”, the 2007-2013 Innovative Regional Strategy (SRI) and the trend of the bioinformatic industries, all seem to confirm the need for considerable investments in the fields covered by the project. The market of generated assets is the national and international biobanks and the clinical facilities that need to process biological specimens. The project is designed to improve the storing facilities of the clinical partners and to market new systems and operational infrastructure of biobanks. In terms of occupation, we estimate that the design phase shall be carried out by the project partners’ staff who will have an opportunity to increase their skills and by new staff hired for reach appropriate staffing levels in the private facilities and research institutions.

Disseminating project results
Creating a network of biobanks will involve promoting know-how and new technology, new patents and increasing staff in the partners of the project. This will support the creation of R&D groups as spin-off born from the conducted research, thus creating a considerable economic impact on the entire industrial sector in Sicily and beyond.

July 2012 – December 2015
The Ri.MED Foundation is responsible for issues related to the research related to the projects and for the training of the fellowsWith Decree 427/Ric. of July 19, 2012, the Italian Ministry for Education, University and Research (MIUR) approved the rankings for the Plans for Strategic Development and the related projects for improvement of and support to regional public-private partnerships, as submitted for the Title II of the Districts and Laboratories Call (n. 713/Ric. of October 29, 2010). To this call the Ri.MED Foundation submitted two projects in partnership with the CNR IBB Catania Public-Private Laboratory (Principal Partner) – Myrmex (that replaces Wyeth):

– Study of small cyto-protective molecules with application for Alzheimer’s disease and for treatment of diabetes with pancreatic islet transplantation
– Innovative therapeutic approaches focused on biometals in oncology and regenerative medicine

Metals are essential for all forms of life. The alterations in their cell homeostasis are often the cause of serious diseases such as tumors or neurodegenerative pathologies. In particular, copper, zinc and their altered homeostasis are apparently involved in the etiology of several oncology diseases such as lymphoproliferative disorders, and in some forms of mammary gland, prostate, lung and GI tract neoplasia.

The reasons of this altered homeostasis of copper and zinc in cancer patients remains unclear. Studying the mechanisms behind their effects in the cancer processes is therefore particularly complex and important. In a similar context, this project will focus on the molecular events responsible for the altered homeostasis of copper and zinc in colorectal, prostate and thyroid cancer cell types in order to generate new compounds, copper and zing ligands that may act as proapoptotic and antiangiogenic drugs in the field of oncology. An effort will be made to reach a deeper understanding of the mechanisms that allow cancer cells to undergo metal-dependent apoptotis and subsequently testing the proapoptotic effects of new compounds with improved selectivity for cancer cells.

The major part of the study will be conducted on human cancer cell lines and bioptic samples, as these represent the best tools to discover new pharmacology targets. Another section of the project will deal with the regenerative medicine study of the ability of copper to modulate angiogenesis and, particularly, the use of copper in association with biomembranes or calcium phosphate scaffolds for therapeutic angiogenesis induction in tissue regeneration applications. The mechanisms regulating angiogenesis are extremely complex as they involve a high level of variability based on the particular microenvironment in which they are hosted, and also can be considerably altered under pathological situations. The soluble factors and cell sources involved in the angiogenesis processes must be appropriately characterized in order to develop induction strategies to be used in the various regenerative medicine applications. By using materials and molecules for which a pro-angiogenesis activity is known, this study will identify bioproducts functional for bone and cardiac and skin ischemic tissue regeneration. In a similar scope the study envisages the development of hydroxyapatite nanovectors, as new entities with angiogenesis ability.

The Ri.MED Foundation was responsible for issues related to the research related to the projects and for the training of the fellows

January 2011 – June 2015

Fondazione Ri.MED, together with Istituto Zooprofilattico Sperimentale della Sicilia “A. Mirri” and Istituto Sperimentale Zootecnico per la Sicilia, is implementing the creation of a multicentre and interdisciplinary cross-company Institute for preclinical research and molecular imaging (Istituto di Sperimentazione Preclinica e Molecular Imaging): the new institute will carry out the entire process of preclinical testing through an integrated approach, and will translate the progress of biomedical research into patient care.
Bringing results from the bench to the patient’s bedside is a time consuming and challenging process. This includes the deep understanding of the biological mechanisms underlying disease, the scientific validation of the results and the proof of safety and efficacy of the innovative approaches through clinical trials.
ISPEMI will approach the scientific validation and regulatory issues creating a functional and IT network of 3 centres with complementary expertise. The collaboration will cover the research activities and organizational issues, and will also offer the opportunity to benefit from services compliant to current quality requirements.
This makes ISPeMI a unique institution, able to develop products and methods covering virtually all industries and technologies involved in the Healthcare sector. The Institute will carry out a variety of activities with high scientific and technical content, offering good potential for international business opportunities.

Biomedical Research Activities: The opportunity to collaborate with ISMETT (an internationally renowned clinical centre specialized in the study and treatment of end-stage organ diseases) and to benefit from the advice offered by reference bodies on regulatory issues (such as the Italian National Institute of Health “ISS” and the Italian Biological Resource Centre “CNRB”), will strengthen the Institute’s ability to provide products that can be immediately used by biotechnology companies (diagnostic tests, antibodies, gene products, recombinant proteins, etc.) and industries involved in drug therapies and/or advanced treatments (cells, products for tissue engineering and gene therapy).

Training Activities: Thanks to its know-how and expertise, the Institute will be fully qualified to provide consultancy services (e.g. medical and veterinary advice during video-laparoscopic and open-surgery on surgical, microsurgical and experimental embryology techniques), training activities for national and international private and public institutions (management of optical image and radiological equipment for small animals and diagnostics, training highly qualified personnel such as radiology technicians, biologists, physicists and medical doctors), as well as scientific dissemination activities, fostering initiatives focused on cooperation and the dissemination of results, which can spread from Sicily to the entire Mediterranean basin and beyond.

Services Activities: In addition to providing individual services, ISPeMI will be able to perform all steps of the translational process, including preclinical testing in small- and large- size animal models, thus ensuring a quick development of innovative diagnostic and therapeutic approaches that are readily applicable, patentable and marketable.

ISPeMI will provide a wide range of services to private and public entities both in Italy and abroad, ranging from the development of diagnostic technologies (tests for molecular and/or protein biomarkers, diagnostic procedures with smart systems, diagnostic imaging procedures) to products for drug therapy, advanced and interventional therapy (drugs, cell therapy, gene therapy, tissue engineering, experimental surgery, clinical and interventional radiology), provided in accordance with the quality requirements established by current regulations (Quality Management System, GLP and GMP).

A highly qualified multidisciplinary training program is available, as part of the ISPeMI project, to the professionals involved in the Institute’s activities – medical doctors, biologists, veterinarians, technical staff and animal technologists – including an on-the-job training period at the three centres involved, which have been improved with the funds provided by the Italian national operational program (PON) for infrastructure:

• Centre for Molecular Medicine and Molecular Imaging at the Regenerative Medicine and Biomedical Technologies Unit managed by Fondazione Ri.MED and the Department of Diagnostic and Therapeutic Services of ISMETT  includes workshops on cell biology, genomics, proteomics and imaging on cell systems and humans. The Centre includes a bio-banking area (for pathological specimens, cells, nucleic acids). Radiological and endoscopic equipment for human use include an MRI at 3T complete with functional imaging and spectroscopy software, and a system for storing images.
• Centre for Preclinical Research on small size animals at the Istituto Zooprofilattico Sperimentale della Sicilia  includes animal facilities for rodents and lagomorphs, an experimental surgery and microsurgery area, a preclinical testing laboratory for cell biology, genomics and proteomics studies and a molecular imaging laboratory for analysis of experimental small animal models. The molecular imaging laboratory includes a room for magnetic resonance imaging, optical imaging equipment and an ultrasound scanner. The images will be stored and processed in specific workstations equipped with dedicated software.
• Centre for Preclinical Research on large size animals at the Istituto Sperimentale Zootecnico della Sicilia characterised by a swine facility, including Precision Livestock Swine Farming (PLSF) for standardised production of Specific Pathogen Free (SPF) animals, an experimental surgery area which includes the equipment required for radiological and endoscopic procedures, and a bio-banking area (experimental biological samples, cells, nucleic acids, seed bank). Image storage software is also available.

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