Return on investment in science: twenty years of European Commission funded research in Alzheimer's dementia, breast cancer and prostate cancer.

Alzheimer's disease (AD), breast cancer (BC) and prostate cancer (PC) continue to be high in the research and innovation agenda of the European Commission (EC). This is due to their exceptionally large burden to the national health systems, the profound economic effects of opportunity costs attributable to decreased working ability, premature mortality and the ever-increasing demand for both hospital and home-based medical care. Over the last two decades, the EC has been steadily increasing both the number of proposals being funded and the amounts of financial resources being allocated to these fields of research. This trend has continued throughout four consecutive science funding cycles, namely framework programme (FP)5, FP6, FP7 and Horizon 2020 (H2020). We performed a retrospective assessment of the outputs and outcomes of EC funding in AD, BC and PC research over the 1999-2019 period by means of selected indicators. These indicators were assessed for their ability to screen the past, present and future for an array of causal relationships and long-term trends in clinical, epidemiological and public health sphere, while considering also the broader socioeconomic impact of funded research on the society at large. This analysis shows that public-private partnerships with large industry and university-based consortia have led to some of the most impactful proposals being funded over the analysed time period. New pharmaceuticals, small molecules and monoclonal antibodies alike, along with screening and prevention, have been the most prominent sources of innovation in BC and PC, extending patients' survival and enhancing their quality of life. Unlike oncology, dementia drug development has been way less successful, with only minor improvements related to the quality of supportive medical care for symptoms and more sensitive diagnostics, without any ground-breaking disease-modifying treatment(s). Significant progresses in imaging diagnostics and nanotechnology have been largely driven by the participation of medical device industry multinational companies. Clinical trials funded by the EC were conducted, leading to the development of brand-new drug molecules featuring novel mechanisms of action. Some prominent cases of breakthrough discoveries serve as evidence for the European capability to generate cutting-edge technological innovation in biomedicine. Less productive areas of research may be reconsidered as priorities when shaping the new agenda for forthcoming science funding programmes.

Drug evaluation in children 10years after the European pediatric regulation current challenges and perspectives.

The European pediatric regulation, that entered into force in June 2007 with the objectives to improve the health of children in Europe, dramatically changed the regulatory environment of paediatric drug evaluation in Europe. The recent 10years European medicines agency (EMA) report showed that the number of paediatric trials increased and that 238 new medicines and indications for use in children were authorised in the EU. However, results remain constrated and futur developments require european collaborations beween all experts in developmental pharmacology, drug evaluation and trial conduct, training, all aspects already considered in different EU paediatric programs.

Early Intraocular Pressure Control Via Capsule Revision of a Failed Valved Aqueous Shunt During Concurrent Placement of a Nonvalved Aqueous Shunt.

PURPOSE: To describe the novel strategy of performing a concurrent capsule revision of a failed pre-existing valved aqueous shunt with implantation of an additional nonvalved aqueous shunt for early postoperative intraocular pressure (IOP) control. DESIGN: Case report of a single patient. RESULTS: An 87-year-old man with severe primary open-angle glaucoma in both eyes presented to our clinic. His pseudophakic left eye had a failed superonasal trabeculectomy and an encapsulated superotemporal Ahmed FP7 (New World Medical) aqueous shunt in the anterior chamber. He had previously undergone micropulse cyclophotocoagulation 3 times and excisional goniotomy. Visual acuity in his left eye was 20/30, and IOP was 24 mmHg on 4 topical IOP-lowering medications. An inferonasal Baerveldt 350 (Advanced Medical Optics) aqueous shunt was placed with concurrent revision of the Ahmed capsule. A large block of capsule tissue was excised from the surface of the plate, and 20 mg of subtenon triamcinolone acetonide (Kenalog, Bristol-Myers Squibb) was injected overlying the plate. His IOP ranged between 6 and 15 mmHg in the immediate postoperative period. There were no hypotony-associated complications at any time point. At postoperative month 18, his IOP was 10 mmHg on zero medications. CONCLUSIONS: In patients with a failed valved aqueous shunt undergoing an additional nonvalved aqueous shunt, a concurrent capsule revision of the valved aqueous shunt can provide early IOP lowering before the nonvalved tube opens.

Toll-like receptor 4 antagonist FP7 alleviates lipopolysaccharide-induced septic shock via NF-kB signaling pathway.

Septic shock is the most severe complication of sepsis occurs when body has an overwhelming response to infection, making it the most prevalent cause of deaths in surgical intensive-care units. Therefore, it is urgent to understand its pathogenesis and develop new therapeutic candidate drugs for septic shock. Here, we explored the effect of FP7, an antagonist of Toll-like receptor 4 (TLR4), in the septic shock. First, we injected mice with FP7 and found that FP7 had no effect on immune cells. Then, bone marrow-derived macrophages (BMDMs) isolated from mice were pretreated with FP7 followed by lipopolysaccharide (LPS) stimulation, and FP7 specifically suppressed LPS-induced inflammatory responses in BMDMs via Nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) signaling pathway, with no effect on other TLRs-mediated inflammations. Finally, we injected mice with LPS and D-galactosamine to induce septic shock, followed by the treatment of FP7, and FP7 significantly increased survival rate, improved lung necrosis, and inhibited the secretions of proinflammatory cytokines in the mice with septic shock. Therefore, our study suggested that FP7 had a protective role in septic shock and it might serve as a promising therapeutic candidate drug to treat septic shock.

Co-substrate-mediated utilization of high concentration of phenol by Aspergillus niger FP7 and reduction of its phytotoxicity on Vigna radiata L.

Phenol and its derivatives behave as mutagens, teratogens and carcinogens inducing adverse physiological effects and are considered environmental hazards. The present study focuses on high concentration phenol utilization by Aspergillus niger FP7 under various physicochemical parameters. The soil remediation potential of the culture for reducing phenol toxicity against Vigna radiata L. seed germination was also evaluated along with the extent of phenol utilization using high-performance liquid chromatography. Aspergillus niger FP7 showed phenol tolerance up to 1000 mg/l, beyond which there was a sharp reduction in phenol utilization. Supplementation of the mineral salt medium with glucose and peptone and application of a 100 rpm agitation rate enhanced phenol utilization (up to 88.3%). Phenol utilization efficiency decreased (up to 29.6%) when cadmium and mercury salts were present, but the same improved (59.4-75.5%) by the incorporation of cobalt, copper and zinc salts. Vigna radiata L. seeds sown in the non-augmented soil revealed a 3.27% germination index, and with fungal augmentation, the germination index improved (97.3%). The non-augmented soil demonstrated 3.1% phenol utilization, while for the augmented soil, the utilization was 79.3%. Based on the phytotoxicity study and chromatographic analysis, it could be inferred that Aspergillus niger FP7 significantly enhanced phenol utilization in soil. In the future, Aspergillus niger FP7 could be of potential use in bioremediation of sites polluted with high concentrations of phenol.

A One-Year Follow-Up of Two Ahmed Glaucoma Valve Models (S2 and FP7) for Refractory Glaucoma: A Prospective Randomized Trial.

AIM: To compare a range of clinical outcome variables (intraocular pressure, glaucoma medications, visual acuity, and complications) between two Ahmed glaucoma valve (AGV) models (S2 and FP7). METHODS: This was a prospective and randomized clinical trial. Fifty-six patients with refractory glaucoma were randomly assigned to be implanted with either a polypropylene (S2) or silicone (FP7) Ahmed glaucoma valve. The primary outcome measure was a surgical success, defined as an IOP ≤ 16 mm Hg (without medication), and guarded success, defined as a controlled IOP ≤ 16 mmHg (with medication). Failure was defined as when the IOP lay outside of the successful range on two consecutive visits (>16 mmHg, despite medication). RESULTS: Mean follow-up period was 398.42 ± 12.34 days (range, 380-420 days) for the S2 group and 401.75 ± 9.78 days (range, 385-420 days) for the FP7 group; these values were not significantly different (P = 0.27). After 12 months of follow-up, the baseline IOP (45.42 mmHg) fell significantly to 16.14 mmHg in the S2 group (p < 0.000); there was also a significant reduction in IOP in the FP7 group (from 44.17 mmHg to 15.18 mmHg in FP7 group, p < 0.000). At the last follow-up examination, the mean IOP in the S2 group was 16.14 ± 3.18 mmHg, while that of the FP7 group was 15.18 ± 2.75 mmHg; there was no significant difference between the two groups with this respect (p = 0.23). The mean number of medications used by patients in the S2 and FP7 groups was 2.92 ± 1.27 and 2.75 ± 1.43, respectively; there was no significant difference between the two groups with this respect (p = 0.32). There was no significant difference between the FP7 and S2 groups with regard to their relative success rate (17.89% [5/28] versus 10.7% [3/28], respectively; p = 0.38). CONCLUSION: Our data show that the S2 and FP7 models of AGV were both effective in lowering IOP and reducing the need for glaucoma medications. Although these two AGV models had similar dimensions, they were constructed from different materials. However, there were no significant clinical differences between the S2 and FP7 AGV groups after 12 months of follow-up. Furthermore, our data indicate that bleb encapsulation was the primary factor responsible for failure rate and the need for glaucoma medication in both the S2 and FP7 groups. Our analysis further indicates that the S2 and FP7 Ahmed valves are associated with a high risk of failure when considered as a first-line therapy for cases experiencing trabeculectomy. CLINICAL TRIAL REGISTRATION: NCT04214847.

Comparison of Silicone- and Porous-Plate Ahmed Glaucoma Valves.

PURPOSE: Our aim was to evaluate and compare the clinical outcomes after implantation of the silicone-plate (model FP7) and porous polyethylene-plate (model M4) Ahmed Glaucoma Valves. PATIENTS AND METHODS: This was a prospective, multicenter, comparative series. A total of 52 eyes (52 patients) were treated with either the silicone or porous plate Ahmed Glaucoma Valve implant. Hypertensive phase was defined as intraocular pressure >21 mmHg during the first 3 months postoperatively. Success was defined as 5 mmHg ≤intraocular pressure ≤21 mmHg (with or without additional glaucoma medications), without loss of light perception and without additional glaucoma procedures. Patients were monitored for 1 year after surgery. RESULTS: The pre-operative intraocular pressure was 29.9 ± 6.6 mmHg and 33.8 ± 10.5 in the silicone-plate and porous-plate groups, respectively (P = 0.118). At 12 months after surgery, the mean intraocular pressure was 13.6 ± 4.7 mmHg in the silicone-plate group and 17.9 ± 10.9 mmHg in the porous-plate group (P = 0.141). The mean number of glaucoma medications at 12 months was 1.64 ± 1.40 mmHg and 1.89 ± 1.54 mmHg in the silicone- and porous-plate groups, respectively (P = 0.605). Hypertensive phase was not significantly different in the two groups (50.0% of the silicone-plate and 57.7% of the porous-plate groups, P = 0.578). At 12 months after surgery, the percent success for the silicone-plate and porous-plate groups was 88.5% and 53.8%, respectively (P = 0.005). Complications were similar in the two groups. CONCLUSION: The porous-plate Ahmed Glaucoma Valve showed similar average intraocular pressure reduction compared with the silicone-plate model. At 12 months after surgery, there was a significantly lower success rate in the porous-plate compared with the silicone-plate group.

Recent advances in methodology for clinical trials in small populations: the InSPiRe project.

Where there are a limited number of patients, such as in a rare disease, clinical trials in these small populations present several challenges, including statistical issues. This led to an EU FP7 call for proposals in 2013. One of the three projects funded was the Innovative Methodology for Small Populations Research (InSPiRe) project. This paper summarizes the main results of the project, which was completed in 2017.The InSPiRe project has led to development of novel statistical methodology for clinical trials in small populations in four areas. We have explored new decision-making methods for small population clinical trials using a Bayesian decision-theoretic framework to compare costs with potential benefits, developed approaches for targeted treatment trials, enabling simultaneous identification of subgroups and confirmation of treatment effect for these patients, worked on early phase clinical trial design and on extrapolation from adult to pediatric studies, developing methods to enable use of pharmacokinetics and pharmacodynamics data, and also developed improved robust meta-analysis methods for a small number of trials to support the planning, analysis and interpretation of a trial as well as enabling extrapolation between patient groups. In addition to scientific publications, we have contributed to regulatory guidance and produced free software in order to facilitate implementation of the novel methods.

Antibiotic-producing Pseudomonas fluorescens mediates rhizome rot disease resistance and promotes plant growth in turmeric plants.

Rhizome rot of turmeric caused by Pythium aphanidermatum is a major threat to turmeric-cultivating areas of India. This study intends to evaluate the performance of fluorescent pseudomonads against Rhizome rot disease and understand the resistance mechanism in Turmeric plants. Fluorescent pseudomonads were screened against Pythium aphanidermatum using dual culture. Selected strains were evaluated for the performance of growth promoting attributes and the presence of antibiotic genes through PCR analysis. Strain FP7 recorded the maximum percent inhibition of P. aphanidermatum under in vitro conditions. Strains FP7 and TPF54 both increased plant growth in turmeric plants in vitro. Strain FP7 alone contained all the evaluated antibiotic biosynthetic genes. Talc and liquid-based formulations were prepared with effective strain and tested for its biocontrol activities under both glasshouse and field conditions. Enzymatic activities of the induced defense enzymes such as PO, PPO, PAL, CAT and SOD were estimated and subjected to spectrophotometric analysis. A combination of rhizome dip and soil drench of FP7 liquid formulation treatment remarkably recorded the minimum disease incidence, higher defense enzymes, maximum plant growth and yield under glasshouse and field conditions. Application of strain FP7 increased the defense molecules, plant growth and yield in turmeric plants thereby reducing the incidence of rhizome rot disease. Moreover, this study has a potential to be adopted for sustainable and eco-friendly turmeric production.

Co-administration of Antimicrobial Peptides Enhances Toll-like Receptor†4 Antagonist Activity of a Synthetic Glycolipid.

This study examines the effect of co-administration of antimicrobial peptides and the synthetic glycolipid FP7, which is active in inhibiting inflammatory cytokine production caused by TLR4 activation and signaling. The co-administration of two lipopolysaccharide (LPS)-neutralizing peptides (a cecropin A-melittin hybrid peptide and a human cathelicidin) enhances by an order of magnitude the potency of FP7 in blocking the TLR4 signal. Interestingly, this is not an additional effect of LPS neutralization by peptides, because it also occurs if cells are stimulated by the plant lectin phytohemagglutinin, a non-LPS TLR4 agonist. Our data suggest a dual mechanism of action for the peptides, not exclusively based on LPS binding and neutralization, but also on a direct effect on the LPS-binding proteins of the TLR4 receptor complex. NMR experiments in solution show that peptide addition changes the aggregation state of FP7, promoting the formation of larger micelles. These results suggest a relationship between the aggregation state of lipid A-like ligands and the type and intensity of the TLR4 response.

Innovation Partnership for a Roadmap on Vaccines in Europe (IPROVE): A vision for the vaccines of tomorrow.

A clear vision for vaccines research and development (R&D) is needed if Europe is to continue to lead the discovery of next generation vaccines. Innovation Partnership for a Roadmap on Vaccines in Europe (IPROVE) is a collaboration between leading vaccine experts to develop a roadmap setting out how Europe can best invest in the science and technology essential for vaccines innovation. This FP7 project, started in December 2013, brought together more than 130 key public and private stakeholders from academia, public health institutes, regulators, industry and small and medium-sized enterprises to determine and prioritise the gaps and challenges to be addressed to bolster innovation in vaccines and vaccination in Europe. The IPROVE consultation process was structured around seven themes: vaccine R&D, manufacturing and quality control, infrastructure, therapeutic vaccines, needs of small and medium-sized enterprises, vaccines acceptance and training needs. More than 80 recommendations were made by the consultation groups, mainly focused on the need for a multidisciplinary research approach to stimulate innovation, accelerated translation of scientific knowledge into technological innovation, and fostering of real collaboration within the European vaccine ecosystem. The consultation also reinforced the fact that vaccines are only as good as their vaccine implementation programmes, and that more must be done to understand and address vaccination hesitancy of both the general public and healthcare professionals. Bringing together a wide range of stakeholders to work on the IPROVE roadmap has increased mutual understanding of their different perspectives, needs and priorities. IPROVE is a first attempt to develop such a comprehensive view of the vaccine sector. This prioritisation effort, aims to help policy-makers and funders identify those vaccine-related areas and technologies where key investment is needed for short and medium-long term success.

The synthetic glycolipid-based TLR4 antagonist FP7 negatively regulates in vitro and in vivo haematopoietic and non-haematopoietic vascular TLR4 signalling.

TLRs, including TLR4, have been shown to play a crucial role in cardiovascular inflammatory-based diseases. The main goal of this study was to determine the potential of FP7, a synthetic glycolipid active as a TLR4 antagonist, to modulate haematopoietic and non-haematopoietic vascular TLR4 pro-inflammatory signalling. HUVEC, human THP-1 monocytes, THP-1-derived macrophages, mouse RAW-264.7 macrophages and Angiotensin II-infused apolipoprotein E-deficient mice were in vitro and in vivo models, respectively. Western blotting, Ab array and ELISA approaches were used to explore the effect of FP7 on TLR4 functional activity in response to bacterial LPS ( in vitro) and endogenous ligands of sterile inflammation ( in vitro and in vivo). Following activation of TLR4, in vitro and in vivo data revealed that FP7 inhibited p38 MAPK and p65 NF-kB phosphorylation associated with down-regulation of a number of TLR4-dependent pro-inflammatory proteins. In addition to inhibition of LPS-induced TLR4 signalling, FP7 negatively regulated TLR4 activation in response to ligands of sterile inflammation (hydroperoxide-rich oxidised LDL, in vitro and Angiotensin II infusion, in vivo). These results demonstrate the ability of FP7 to negatively regulate in vitro and in vivo haematopoietic and non-haematopoietic vascular TLR4 signalling both in humans and mice, suggesting the potential therapeutic use of this TLR4 antagonist for pharmacological intervention of vascular inflammatory diseases.

Evidence based policy making in the European Union: the role of the scientific community.

In the times when the acquis of the European Union (EU) has developed so far as to reach a high level of technical complexity, in particular in certain policy fields such as environmental legislation, it is important to look at what kind of information and data policy decisions are based on. This position paper looks at the extent to which evidence-based decision-making process is being considered in the EU institutions when it comes to adopting legislation in the field of environment at the EU level. The paper calls for closer collaboration between scientists and decision-makers in view of ensuring that correct data is understood and taken into consideration when drafting, amending, negotiating and adopting new legal texts at all levels of the EU decision-making process. It concludes that better awareness of the need for such collaboration among the decision-makers as well as the scientific community would benefit the process and quality of the final outcomes (legislation).

A case study to optimise and validate the brine shrimp Artemia franciscana immobilisation assay with silver nanoparticles: The role of harmonisation.

Brine shrimp Artemia sp. has been recognised as an important ecotoxicity and nanotoxicity test model organism for salt-rich aquatic environments, but currently there is still no harmonised testing protocol which would ensure the comparable results for hazard identification. In this paper we aimed to design the harmonised protocol for nanomaterial toxicity testing using Artemia franciscana and present a case study to validate the protocol with silver nanoparticles (AgNPs). We (i) revised the existing nanotoxicity test protocols with Artemia sp. (ii) optimised certain methodological steps based on the experiments with AgNPs and potassium dichromate (K2Cr2O7) as a soluble reference chemical and (iii) tested the optimised protocol in an international inter-laboratory exercise conducted within the EU FP7 NanoValid project. The intra- and inter-laboratory reproducibility of the proposed protocol with a soluble reference chemical K2Cr2O7 was good, which confirms the suitability of this assay for conventional chemicals. However, the variability of AgNPs toxicity results was very high showing again that nanomaterials are inherently challenging for toxicity studies, especially those which toxic effect is linked to shed metal ions. Among the identified sources for this variability were: the hatching conditions, the type of test plate incubation and the illumination regime. The latter induced variations assumingly due to the changes in bioavailable silver species concentrations. Up to our knowledge this is the first inter-laboratory comparison of the Artemia sp. toxicity study involving nanomaterials. Although the inter-laboratory exercise revealed poor repeatability of AgNPs toxicity results, this study provides valuable information regarding the importance of harmonisation of all steps in the test procedure. Also, the presented AgNPs toxicity case study may serve as a platform for further validation steps with other types of NMs.

An interlaboratory comparison of nanosilver characterisation and hazard identification: Harmonising techniques for high quality data.

Within the FP7 EU project NanoValid a consortium of six partners jointly investigated the hazard of silver nanoparticles (AgNPs) paying special attention to methodical aspects that are important for providing high-quality ecotoxicity data. Laboratories were supplied with the same original stock dispersion of AgNPs. All partners applied a harmonised procedure for storage and preparation of toxicity test suspensions. Altogether ten different toxicity assays with a range of environmentally relevant test species from different trophic levels were conducted in parallel to AgNP characterisation in the respective test media. The paper presents a comprehensive dataset of toxicity values and AgNP characteristics like hydrodynamic sizes of AgNP agglomerates and the share (%) of Ag(+)-species (the concentration of Ag(+)-species in relation to the total measured concentration of Ag). The studied AgNP preparation (20.4±6.8 nm primary size, mean total Ag concentration 41.14 mg/L, 46-68% of soluble Ag(+)-species in stock, 123.8±12.2 nm mean z-average value in dH2O) showed extreme toxicity to crustaceans Daphnia magna, algae Pseudokirchneriella subcapitata and zebrafish Danio rerio embryos (EC50<0.01 mg total Ag/L), was very toxic in the in vitro assay with rainbow trout Oncorhynchus mykiss gut cells (EC50: 0.01-1 mg total Ag/L); toxic to bacteria Vibrio fischeri, protozoa Tetrahymena thermophila (EC50: 1-10 mg total Ag/L) and harmful to marine crustaceans Artemia franciscana (EC50: 10-100 mg total Ag/L). Along with AgNPs, also the toxicity of AgNO3 was analyzed. The toxicity data revealed the same hazard ranking for AgNPs and AgNO3 (i.e. the EC50 values were in the same order of magnitude) proving the importance of soluble Ag(+)-species analysis for predicting the hazard of AgNPs. The study clearly points to the need for harmonised procedures for the characterisation of NMs. Harmonised procedures should consider: (i) measuring the AgNP properties like hydrodynamic size and metal ions species in each toxicity test medium at a range of concentrations, and (ii) including soluble metal salt control both in toxicity testing as well as in Ag(+)-species measurements. The present study is among the first nanomaterial interlaboratory comparison studies with the aim to improve the hazard identification testing protocols.

TRANSVAC research infrastructure - Results and lessons learned from the European network of vaccine research and development.

TRANSVAC was a collaborative infrastructure project aimed at enhancing European translational vaccine research and training. The objective of this four year project (2009-2013), funded under the European Commission's (EC) seventh framework programme (FP7), was to support European collaboration in the vaccine field, principally through the provision of transnational access (TNA) to critical vaccine research and development (R&D) infrastructures, as well as by improving and harmonising the services provided by these infrastructures through joint research activities (JRA). The project successfully provided all available services to advance 29 projects and, through engaging all vaccine stakeholders, successfully laid down the blueprint for the implementation of a permanent research infrastructure for early vaccine R&D in Europe.

Stakeholder attitudes towards cumulative and aggregate exposure assessment of pesticides.

This study evaluates the attitudes and perspectives of different stakeholder groups (agricultural producers, pesticide manufacturers, trading companies, retailers, regulators, food safety authorities, scientists and NGOs) towards the concepts of cumulative and aggregate exposure assessment of pesticides by means of qualitative in-depth interviews (n = 15) and a quantitative stakeholder survey (n = 65). The stakeholders involved generally agreed that the use of chemical pesticides is needed, primarily for meeting the need of feeding the growing world population, while clearly acknowledging the problematic nature of human exposure to pesticide residues. Current monitoring was generally perceived to be adequate, but the timeliness and consistency of monitoring practices across countries were questioned. The concept of cumulative exposure assessment was better understood by stakeholders than the concept of aggregate exposure assessment. Identified pitfalls were data availability, data limitations, sources and ways of dealing with uncertainties, as well as information and training needs. Regulators and food safety authorities were perceived as the stakeholder groups for whom cumulative and aggregate pesticide exposure assessment methods and tools would be most useful and acceptable. Insights obtained from this exploratory study have been integrated in the development of targeted and stakeholder-tailored dissemination and training programmes that were implemented within the EU-FP7 project ACROPOLIS.