Mutation-based, short-term "neoadjuvant" treatment allows resectability in stage IVB and C anaplastic thyroid cancer.

INTRODUCTION: Few available data indicate that a mutation-based "neoadjuvant" therapy in advanced anaplastic thyroid carcinoma (ATC) might convert an initially unresectable primary tumor to resectable and optimize local tumor control. We evaluated a preoperative short-term "neoadjuvant" therapy with a BRAF-directed therapy or, in case of BRAF non-mutated tumors, an mKI/checkpoint inhibitor combination in three patients with ATC stage IVB and C. METHODS: In the context of preoperative diagnostics, immunohistochemistry (IHC) assessment and genetic analysis was started as soon as possible. The antiangiogenetic therapy with lenvatinib was immediately after diagnosis of ATC started as bridging therapy. In case of a BRAF-mutated ATC, a combination therapy of dabrafenib and trametinib, in case of BRAF-wildtype ATC a combination of pembrolizumab and lenvatinib was given for 4 weeks. If re-staging has shown a significant therapy response due to a decrease in size of > 50%, surgical resection was reconsidered. A primary tumor resection was performed first. As a second step, limited distant metastasis have been resected approximately 4 weeks after thyroid surgery. After postoperative recovery, the targeted systemic therapy was continued. PATIENTS: Two patients presented with BRAF-wildtype ATC stage IVC, one with BRAF-mutated ATC stage IVB. All patients were evaluated by surgery, nuclear medicine and oncology upon diagnosis of ATC. RESULTS: In all three cases, the "neoadjuvant" therapy induced a dramatic response and led to local resectability in primarily non-resectable ATC stage IVB or C. We have chosen for the first time a short-term "neoadjuvant" treatment period to reduce the risk of bleeding and/or fistula due to potential rapid tumor shrinkage. The results of surgery after only short-term "neoadjuvant" therapy showed two R0 und one R1 resections. Postoperative histopathological findings confirmed an extent of tumor necrosis or regressive fibrotic tissue between 60 and > 95% in our patients. CONCLUSIONS: A short-term mutation-based "neoadjuvant" therapy can achieve local resectability in initially unresectable ATC stage IVB or C. A neoadjuvant treatment period of about 4 weeks seems to show similar response as a treatment duration of at least 3 months.

CD11c+ dendritic cells mediate antigen-specific suppression in extracorporeal photopheresis.

Extracorporeal photopheresis (ECP) represents one of the most widespread and effective cell therapies for graft-versus-host disease and other T cell-mediated disorders. However, the key factors affecting the therapeutic efficacy of ECP remain unclear. We hypothesized that therapeutic effects are mediated by ECP-treated antigen-presenting dendritic cells (DC). To test this hypothesis, we used the experimental model of contact hypersensitivity (CHS). The ECP's therapeutic activity improved when the total cell dose of the ECP-treated cells was increased. We used different haptens during sensitization to demonstrate that the anti-inflammatory activity of ECP is antigen-specific. This confirmed the hypothesis that professional antigen-presenting cells are involved in the mode of action. Also, the ECP's therapeutic activity was abrogated by the depletion of CD11c+ DC, which represents fewer than 1% of all the ECP-exposed cells. Finally, we confirm the critical importance of CD11c+ DC for ECP activity by showing that only a few purified CD11c+ DC are sufficient to mediate its therapeutic effect. The finding that ECP-treated, physiological antigen-presenting DC alone mediate antigen-specific modulation of a pathological immune response may result in better-targeted interventions when treating patients.

Ultrasmall Moment Incommensurate Spin Density Wave Order Masking a Ferromagnetic Quantum Critical Point in NbFe_{2}.

In the metallic magnet Nb_{1-y}Fe_{2+y}, the low temperature threshold of ferromagnetism can be investigated by varying the Fe excess y within a narrow homogeneity range. We use elastic neutron scattering to track the evolution of magnetic order from Fe-rich, ferromagnetic Nb_{0.981}Fe_{2.019} to approximately stoichiometric NbFe_{2}, in which we can, for the first time, characterize a long-wavelength spin density wave state burying a ferromagnetic quantum critical point. The associated ordering wave vector q_{SDW}=(0,0,l_{SDW}) is found to depend significantly on y and T, staying finite but decreasing as the ferromagnetic state is approached. The phase diagram follows a two-order-parameter Landau theory, for which all of the coefficients can now be determined. Our findings suggest that the emergence of spin density wave order cannot be attributed to band structure effects alone. They indicate a common microscopic origin of both types of magnetic order and provide strong constraints on related theoretical scenarios based on, e.g., quantum order by disorder.

[Rare diseases recognizable from blood smears]. / Seltene Erkrankungen am Blutbild erkennen.

The examination of peripheral blood smears is not only essential for the differential diagnostics of hematological diseases but can also provide important indications for general internal diseases, infections, hereditary diseases and poisoning. By the systematic analysis of a blood smear for alterations to thrombocytes, erythrocytes and leukocytes, a blood smear investigation can make a decisive contribution to the formulation of a diagnosis. In this way evidence of rare diseases can also be gained when taking the corresponding clinical findings into consideration.

Heat-labile Escherichia coli toxin enhances the induction of allergen-specific IgG antibodies in epicutaneous patch vaccination.

Epicutaneous allergen-specific immunotherapy (EPIT) is proposed as an alternative route for allergen-specific immunotherapy (AIT). The induction of allergen-specific blocking IgG antibodies represents an important mechanism underlying AIT, but has not been investigated for EPIT. Here, we compared the induction of allergen-specific blocking IgG in outbred guinea pigs which had been immunized with recombinant birch pollen allergen Bet v 1 using patch delivery system (PDS) with or without heat-labile toxin (LT) from Escherichia coli or subcutaneously with aluminum hydroxide (Alum)-adsorbed rBet v 1. Only subcutaneous immunization with Alum-adsorbed rBet v 1 and epicutaneous administration of rBet v 1 with PDS in combination with LT from E. coli induced allergen-specific IgG antibodies blocking allergic patients' IgE, but not immunization with rBet v 1 via PDS alone. Our results suggest that patch vaccination with rBet v 1 in combination with LT may be a promising strategy for allergen-specific immunotherapy against birch pollen allergy.

Amb a 1 isoforms: Unequal siblings with distinct immunological features.

BACKGROUND: Ragweed pollen represents a major allergy risk factor. Ragweed extracts contain five different isoforms of the major allergen Amb a 1. However, the immunological characteristics of Amb a 1 isoforms are not fully investigated. Here, we compared the physicochemical and immunological properties of three most important Amb a 1 isoforms. METHODS: After purification, the isoforms were physicochemically characterized, tested for antibody binding and induction of human T-cell proliferative responses. Their immunological properties were further evaluated in vitro and in vivo in a mouse model. RESULTS: Amb a 1 isoforms exhibited distinct patterns of IgE binding and immunogenicity. Compared to Amb a 1.02 or 03 isoforms, Amb a 1.01 showed higher IgE-binding activity. Isoforms 01 and 03 were the most potent stimulators of patients' T cells. In a mouse model of immunization, Amb a 1.01 induced higher levels of IgG and IgE antibodies when compared to isoforms 02 and 03. Interestingly, ragweed-sensitized patients also displayed an IgG response to Amb a 1 isoforms. However, unlike therapy-induced antibodies, sensitization-induced IgG did not show IgE-blocking activity. CONCLUSION: The present study showed that naturally occurring isoforms of Amb a 1 possess different immunogenic and sensitizing properties. These findings should be considered when selecting sequences for molecule-based diagnosis and therapy for ragweed allergy. Due to its high IgE-binding activity, isoform Amb a 1.01 should be included in diagnostic tests. In contrast, due to their limited B- and T-cell cross-reactivity patterns, a combination of different isoforms might be a more attractive strategy for ragweed immunotherapy.

The influence of transcranial alternating current stimulation (tACS) on fluid intelligence: An fMRI study.

The past decades have witnessed a huge interest in uncovering the neural bases of intelligence (e.g., Stelmack, & Houlihan, 1995; Stelmack, Knott, & Beauchamp, 2003). This study investigated the influence of transcranial alternating current stimulation (tACS) on fluid intelligence performance and corresponding brain activation. Previous findings showed that left parietal theta tACS leads to a transient increase in fluid reasoning performance. In an attempt to extend and replicate these findings, we combined theta tACS with fMRI. In a double-blind sham-controlled experiment, N = 20 participants worked on two intelligence tasks (matrices and paper folding) after theta tACS was applied to the left parietal cortex. Stimulation-induced brain activation changes were recorded during task processing using fMRI. Results showed that theta tACS significantly increased fluid intelligence performance when working on difficult items in the matrices test; no effect was observed for the visuo-spatial paper folding test. Whole-brain analyses showed that left parietal brain stimulation was accompanied by lower activation in task-irrelevant brain areas. Complemental ROI analyses revealed a tendency towards lower activation in the left inferior parietal cortex. These findings corroborate the functional role of left parietal theta activity in fluid reasoning and are in line with the neural efficiency hypothesis.

[Immunotherapy of cancer with checkpoint inhibitors : Not only in malignant melanoma]. / Immuntherapie von Tumorerkrankungen mit Checkpoint-Inhibitoren : Nicht nur beim malignen Melanom.

The newest weapon in cancer therapy is checkpoint inhibition, which is the result of basic immunology research. The success of this therapy is based on the fact that upon light microscopy, many solid tumors harbor lymphocytic cells infiltrating the tumor (TILs), and in many solid tumors, the presence of these TILs are prognostic. Ipilimumab was the first monoclonal antibody developed against a target present on T cells after becoming activated, CTLA-4. In malignant melanoma, ipilimumab showed its beneficial effect as compared to a placebo peptide. However, the therapy with this antibody harbors significant toxicity. Meanwhile, other targets such as PD-1, also expressed on (late) activated T cells, were identified, and therapies with antibodies inhibiting PD-1/PD-L1 are less toxic. Although these antibodies show response only in a minority of patients, the benefit seems durable in some of these patients. In solid tumors such as melanoma or non-small cell lung cancer (NSCLC), treatment with PD-1 inhibitors has resulted in a significant prolongation of survival, even in first-line treatment. As these drugs have been approved in many indications, it is important to know the drugs and side effects. Resistance towards these drugs are caused by low expression of the natural ligand, PD-L1, in the tumor tissue, as well as acquired loss of signal transduction of interferon-related genes such as JAK1 or JAK2, respectively. Also new in cancer therapy are bispecific T cell engager monoclonal antibodies (BiTEs) such as blinatumomab, and autologous chimeric antigen receptor-modified T cells (CAR-Ts). The later have proven their efficacy mainly in hematological neoplasias such as precursor-B-ALL. The dramatic costs of all these new drugs will have an enormous impact on the health care systems in the near future.

[Choosing wisely recommendations in hematology and oncology]. / Klug-entscheiden-Empfehlungen in der Hämatologie und Onkologie.

Many new diagnostic and therapeutic options have been introduced in the field of hematology and medical oncology during recent years. Rational treatment recommendations are thus of even greater importance. Five presumably underused measures are recommended (positive recommendations), primarily pertaining to supportive therapy, but also concerning the selective use of molecular diagnostics. Recommendations to avoid unnecessary procedures (negative recommendations) involve a possible excessive use of anticancer therapy and imaging, and insufficiently selective use of growth factors, antiemetics, and targeted therapies.

Standardization of allergen products: 2. Detailed characterization of GMP-produced recombinant Phl p 5.0109 as European Pharmacopoeia reference standard.

BACKGROUND: The Biological Standardization Programme of the European Directorate for Quality of Medicines and Healthcare (EDQM) aims at the establishment of well-characterized reference standards based on recombinant allergens and validated assays for the quantification of major allergen content. The objective of this study was to examine the detailed physicochemical and immunological characterization of recombinant Phl p 5.0109, the second available allergen reference standard. METHODS: Recombinant Phl p 5.0109 PP5ar06007 was produced under GMP conditions and analyzed by an array of physicochemical and immunological methods for identity, quantity, homogeneity, and folding stability in bulk solution, as well as thermal denaturation, aggregation state, and biological activity when formulated for long-time storage. RESULTS: PP5ar06007 revealed as a highly homogeneous, monomeric, well-folded preparation of rPhl p 5.0109, as documented by mass spectrometry, SDS-PAGE, isoelectric focusing, size-exclusion chromatography with light scattering, circular dichroism, and infrared spectroscopy. Upon storage at +4°C, PP5ar06007 retained the monomeric state for at least 2 months. A protein quantity of 1.56 ± 0.03 mg/ml was determined by amino acid analysis in PP5ar06007, and its biological activity was shown to be comparable to natural Phl p 5 in terms of basophil activation and T-cell reactivity. CONCLUSIONS: Recombinant Phl p 5.0109 PP5ar06007 was characterized extensively at the physicochemical and immunological level. It revealed to be a highly stable, monomeric, and immunologically equivalent of its natural counterpart. PP5ar06007 is now available as European Pharmacopoeia allergen reference standard for grass pollen products.

[Economic Short-Term Cost Model for Stereotactic Radiotherapy of Neovascular AMD]. / Ökonomisches Kostenmodell zur Radiotherapie der neovaskulären AMD.

OBJECTIVES: Stereotactic radiation therapy (Oraya, OT) is available as a second line therapy for patients who, despite intensive anti-VEGF therapy for neovascular AMD, do not show an improvement in CNV. As OT is expensive (5,308 €), the short term economics for starting this therapy were investigated. METHODS: A short-term cost model was set up in MS Excel with a two year time horizon. On the basis of the data of the randomised, controlled INTREPID pivotal trial and current treatment practice in Germany, the costs were compared of conventional anti-VEGF therapy, with or without a single OT treatment. Patients with an active lesion after initial anti-VEGF therapy and a maximum lesion diameter ≤ 4 mm were included. Modeled cost components/aspects were direct savings from injection number, control follow-up examinations and aids, as well as anti-VEGF switches. Costs for Germany were employed and a univariate sensitivity analysis was performed to address the existing uncertainty. RESULTS: For the patients with a maximum AMD lesion diameter ≤ 4 mm and a macula volume > 7.4 mm(3), the INTREPID trial showed a mean reduction of 3.68 intravitreal injections for 16 Gy radiation versus sham over a time period of 2 years. These 3.68 IVM result in ~ 4,500 € direct cost savings. Moreover, due to the higher response rate with 16 Gy radiation, the number of follow-up visits and aids can be reduced, which results in savings between 207 € and 1,224 € over 2 years. After radiation, fewer anti-VEGF switches for low or non-responders are expected, which is modeled to result in ~ 1.7 fewer injections over 2 years. Due to overall fewer injections, fewer endophthalmitis cases would be expected. However, endophthalmitis and microvascular abnormalities, which can be observed in a few cases, are associated with low or non-quantifiable costs in this cost-cost comparison model. In summary, cost reductions of between 6,400 and 8,500 € are predicted in the model over two years, which have to be compared to the costs of a single application of OT. CONCLUSIONS: The short-term economic analysis shows that anti-VEGF therapy combined with OT results in savings above the costs for OT itself over a 2 year time horizon. Overall, the approach gives potential cost reductions, if the appropriate indication is followed.

[Molecular tumour therapy]. / Molekulare Tumortherapie.

In recent years, molecular tumour therapy has dramatically improved the treatment of various types of cancer. Molecular therapy is expected to attack malignant cells more specifically with fewer side effects than conventional chemotherapy. Both kinase inhibitors and monoclonal antibodies are key components of today's molecular cancer therapy. These substances cannot fully overcome the major tumour-biological problems, e.g. therapy resistance. However, as can be vividly seen with the example of immune checkpoint inhibitors, the rational design of molecularly designed drugs will considerably change therapeutic practice in oncology, albeit at the expense of exponentially growing health care costs.

[Functional and morphological correlations in macular hole surgery]. / Funktionelle und morphologische Korrelationen in der Makulaforamen-Chirurgie.

BACKGROUND: The purpose of this study is to establish the correlation between functional and morphological aspects before and 12 months after macular hole surgery. METHODS: In this prospective, interventional, consecutive study 16 eyes of 16 patients were included. All eyes received a successful transconjunctival 23-gauge vitrectomy with ILM peeling after initial diagnosis and maximum duration of symptoms of two months. Preoperatively and 3, 6 and 12 months postoperatively determinations of best-corrected visual acuity (logMAR), a 10° microperimetry (MP-1) and a spectral-domain based optical coherence tomography (SD-OCT) examination were performed. The photoreceptor layer (inner and outer segment, IS/OS) was evaluated based on SD-OCT images and correlated with data assessed by microperimetry analysis in the foveal and parafoveal region. RESULTS: After three months a stabilisation of BCVA with regeneration of the IS/OS line, an improvement of the fixation behaviour and the macular sensitivity could be observed. A significant restitution of the IS/OS line was observed after 12 months. Best corrected visual acuity, mean overall macular sensitivity and fixation improved significantly within the twelve month observation period (p < 0.05). Comparison of patients with at least two lines of visual acuity gain with patients having less than two lines of visual acuity gain 12 months after surgery showed no statistically significant difference in regeneration of the IS/OS integrity in the fovea (p = 0.433), but a difference was seen in the parafoveal region. A postoperative visual acuity gain of at least two lines was significantly more often seen in eyes with postoperative continuous IS/OS line in the parafoveal sectors compared to eyes with persistent IS/OS defects (p < 0.02). CONCLUSION: Correlations of morphological and functional improvements can be observed after successful micro-invasive macular hole surgery. The extent of the preoperative IS/OS defect, particularly in the parafoveal region, is a good predictive parameter for the postoperatively obtained macular sensitivity. The prediction of the postoperative visual acuity should not be made on the basis of a single clinical, anatomic finding.

[Complications after allogeneic bone marrow and stem cell transplantation]. / Komplikationen der allogenen Knochenmark- und Stammzelltransplantation.

Since the 1970s there has been an increase in the number of bone marrow and stem cell transplantations as well as a decrease in transplantation-associated fatalities due to improved transplantation techniques and supportive therapy. Annually nearly 50,000 transplantations are conducted worldwide with matched family grafts and matched or sometimes mismatched unrelated donor grafts. The number of long-term survivors is increasing and the late complications of this relatively aggressive therapy are now becoming apparent. This article is essentially concerned with the delayed complications of bone marrow and stem cell transplantations. Despite curing the malignant primary disease the total survival of transplantation patients is reduced. The main reasons are infection, organ dysfunction and therapy-associated secondary neoplasms. Among the high risk factors are total body irradiation, chronic graft versus host disease as well as treatment during childhood. Guidelines for the follow-up care of these long-term survivors were first published in 2006 and then updated in 2011.

Enzyme-based glucose delivery as a high content screening tool in yeast-based whole-cell biocatalysis.

The influence of glucose release on growth and biotransformation of yeasts was examined by using the medium EnBase® Flo in shake flasks. The medium contains a polysaccharide acting as substrate, which is degraded to glucose by the addition of an enzyme. In the present paper, this medium was adapted for the cultivation of yeasts by increasing the complex components (booster) and the enzyme concentrations to guarantee a higher glucose release rate. Important changes were an increase of the complex component booster to 10-15% and an increased glucose release by increasing the enzyme content to 15 U L(-1). The 20 yeasts investigated in the present work showed an improvement of growth and biomass production when cultivated with the EnBase medium in comparison to yeast extract dextrose (YED) medium. Values of optical densities (OD(600)) of approximately 40 AU (corresponding to over 60 g L(-1) wet cell weight) were achieved for all 20 yeast strains tested. During the following screening of the yeasts in whole-cell biotransformation, an improvement of the conversion for 19 out of the 20 yeasts cultivated with the EnBase Flo medium could be observed. The biomass from the EnBase Flo cultivation showed a higher conversion activity in the reduction of 2-butanone to (R/S)-2-butanol. The enantioselectivity (ee) of 15 yeast strains showed an improvement by using the EnBase medium. The number of yeasts with an ee >97% increased from zero with YED to six with EnBase medium. Thus, the use of a glucose release cultivation strategy in the screening process for transformation approaches provides significant benefits compared to standard batch approaches.

Long-term cognitive outcomes of extremely low-birth-weight infants: the influence of the maternal educational background.

AIM: The purpose of the present contribution is to analyse the relationships between perinatal risk factors, social parameters and neurodevelopmental outcomes in extremely low-birth-weight (ELBW) children up to the age of 10-13 years. METHODS: Of 200 live-born ELBW infants, 148 were enrolled in the high-risk infant follow-up programme. Each follow-up visit included a neurodevelopmental examination and an interview with the infant's parents. Multivariate analyses using SPSS (version 17.0, Chicago, IL, USA) were conducted, and a p-value of <0.05 indicated a statistically significant result. RESULTS: The results of the logistic regression analysis of the biological and sociodemographic risk factors illustrated that a low maternal educational background is the most important factor (OR, 21.9) associated with a decreased composite intelligence quotient (IQ) in children between 10 and 13 years old. A Grade III or Grade IV intraventricular haemorrhage (IVH) or periventricular leukomalacia (PVL) were also associated with decreased IQ at the age of 10-13 years (OR, 6.9). These results were confirmed by ANOVAs with repeated measurements. CONCLUSION: Maternal educational background is the strongest predictor of long-term neurodevelopment in ELBW children. The findings emphasize the need for special support and follow-up care services for poorly educated parents.

Budget impact of the Oncotype DX® test compared to other gene expression tests in patients with early breast cancer in Germany.

PURPOSE: Gene expression tests can inform decisions on whether to recommend chemotherapy for patients with HR+, HER2- early breast cancer. The goal of this analysis was to compare treatment costs by an expanded budget impact model of reimbursed gene expression tests in Germany. METHODS: A cost comparison was constructed as an expanded budget impact model to calculate average total costs per patient covered by public health insurance. Based on the strong clinical evidence from the prospective randomized controlled trial TAILORx including more than 10,000 patients with HR+ and node negative breast cancer, the assumption was made that the Oncotype DX® test accurately predicts chemotherapy benefit and clinical outcomes. For the further reimbursed tests (EndoPredict®, MammaPrint®, Prosigna®), results from comparative studies - aligned with prognosis studies - as analyzed in IQWiG Rapid Report D19-01 were applied. RESULTS: The use of the Oncotype DX test led to estimated average savings per patient of 2,500 € vs. EndoPredict, 1,936 € vs. MammaPrint, and 649 € vs. Prosigna. Savings were achieved by reduction of unnecessary chemotherapy use, a consequence of false-positive test results (EndoPredict 73%, MammaPrint 42%, Prosigna 20%). False-negative test results (EndoPredict 5%, MammaPrint 22%, Prosigna 49%) reduced necessary chemotherapies, which initially results in cost savings, but may lead to increased long-term costs associated with management of progressive disease. CONCLUSION: The results from this model suggest that the use of the Oncotype DX test reduces the cost of health care in Germany making it the most cost effective test compared to the further tests.

Long-range crystalline nature of the Skyrmion lattice in MnSi.

We report small angle neutron scattering of the Skyrmion lattice in MnSi using an experimental setup that minimizes the effects of demagnetizing fields and double scattering. Under these conditions, the Skyrmion lattice displays resolution-limited Gaussian rocking peaks that correspond to a magnetic correlation length in excess of several hundred micrometers. This is consistent with exceptionally well-defined long-range order. We further establish the existence of higher-order scattering, discriminating parasitic double scattering with Renninger scans. The field and temperature dependence of the higher-order scattering arises from an interference effect. It is characteristic for the long-range crystalline nature of the Skyrmion lattice as shown by simple mean-field calculations.

MeDALL (Mechanisms of the Development of ALLergy): an integrated approach from phenotypes to systems medicine.

The origin of the epidemic of IgE-associated (allergic) diseases is unclear. MeDALL (Mechanisms of the Development of ALLergy), an FP7 European Union project (No. 264357), aims to generate novel knowledge on the mechanisms of initiation of allergy and to propose early diagnosis, prevention, and targets for therapy. A novel phenotype definition and an integrative translational approach are needed to understand how a network of molecular and environmental factors can lead to complex allergic diseases. A novel, stepwise, large-scale, and integrative approach will be led by a network of complementary experts in allergy, epidemiology, allergen biochemistry, immunology, molecular biology, epigenetics, functional genomics, bioinformatics, computational and systems biology. The following steps are proposed: (i) Identification of 'classical' and 'novel' phenotypes in existing birth cohorts; (ii) Building discovery of the relevant mechanisms in IgE-associated allergic diseases in existing longitudinal birth cohorts and Karelian children; (iii) Validation and redefinition of classical and novel phenotypes of IgE-associated allergic diseases; and (iv) Translational integration of systems biology outcomes into health care, including societal aspects. MeDALL will lead to: (i) A better understanding of allergic phenotypes, thus expanding current knowledge of the genomic and environmental determinants of allergic diseases in an integrative way; (ii) Novel diagnostic tools for the early diagnosis of allergy, targets for the development of novel treatment modalities, and prevention of allergic diseases; (iii) Improving the health of European citizens as well as increasing the competitiveness and boosting the innovative capacity of Europe, while addressing global health issues and ethical issues.