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Background: TAK-063 is an inhibitor of phosphodiesterase 10A (PDE10A), an enzyme highly expressed in medium spiny neurons of the striatum. PDE10A hydrolyzes both cyclic adenosine monophosphate and cyclic guanosine monophosphate and modulates dopamine signaling downstream of receptor activation in both direct and indirect pathways of the striatum. TAK-063 exhibited antipsychotic-like effects in animal models; however, the translatability of these models to the clinical manifestations of schizophrenia and the meaningfulness for new targets such as PDE10A has not been established., Methods: The TAK-063 phase 1 program included a comprehensive translational development strategy with the main objective of determining whether the antipsychotic-like pharmacodynamic effects seen in nonclinical models would translate to human subjects. To evaluate this objective, we conducted a single-rising dose study (84 healthy subjects), a positron emission tomography (PET) study (12 healthy subjects), a functional magnetic resonance imaging blood oxygen level-dependent (BOLD) study (27 healthy subjects), and a multiple-rising dose study that included people with schizophrenia (30 healthy Japanese subjects and 47 subjects with stable schizophrenia). In addition, assessments of cognition and electroencephalography (27 healthy subjects and 47 subjects with stable schizophrenia) were included., Results: PDE10A engagement by TAK-063 was verified with a novel PET radiotracer for use in primates and humans. TAK-063 showed favorable pharmacokinetic and safety profiles in humans, and TAK-063 reduced ketamine-induced changes in electroencephalography and BOLD signaling in animal models and healthy human subjects. In addition, analogous effects on cognition were observed in animal models and human subjects., Conclusions: Overall, the phase 1 results showed some consistent evidence of antipsychotic activity. This translational strategy may be valuable for the future development of novel therapeutic approaches, even when relevant nonclinical models are not available., (© The Author(s) 2020. Published by Oxford University Press on behalf of CINP.)

Progressive myoclonic epilepsies (PMEs) comprise a group of rare disorders of different genetic aetiologies, leading to childhood-onset myoclonus, myoclonic seizures and subsequent neurological decline. One of the genetic causes for PME, a mutation in the gene coding for Golgi SNAP receptor 2 (GOSR2), gives rise to a PME-subtype prevalent in Northern Europe and hence referred to as North Sea Progressive Myoclonic Epilepsy (NS-PME). Treatment for NS-PME, as for all PME subtypes, is symptomatic; the pathophysiology of NS-PME is currently unknown, precluding targeted therapy. Here, we investigated the pathophysiology of NS-PME. By means of chart review in combination with interviews with patients (n = 14), we found heat to be an exacerbating factor for a majority of NS-PME patients (86%). To substantiate these findings, we designed a NS-PME Drosophila melanogaster model. Downregulation of the Drosophila GOSR2-orthologue Membrin leads to heat-induced seizure-like behaviour. Specific downregulation of GOSR2/Membrin in glia but not in neuronal cells resulted in a similar phenotype, which was progressive as the flies aged and was partially responsive to treatment with sodium barbital. Our data suggest a role for GOSR2 in glia in the pathophysiology of NS-PME., (Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.)

Interventional pulmonology (IP) is experiencing a rapid evolution of new technologies. There is a need to develop structured training programs, organized in high volume expert centers in order to improve trainee education, and including the development of validated metrics for their competency assessment. Concerning teaching methods, a gradual progression from theory to practice, using new teaching techniques, including live sessions and low and high-fidelity simulation, flipped classroom models and problem-based learning (PBL) exercises would provide a training setting more suitable for our current need to improve skills and update professionals. Training programs should be learner-centered and competence-oriented, as well as being based on a spiral-shaped approach in which the same subject is addressed many times, from new and different perspectives of knowledge, ability, behavior and attitude, until the trainee has demonstrated a high degree of skill and professionalism. Furthermore there is a need to standardize the training programs as guide for physicians wishing to undertake a gradual and voluntary improvement of their own competencies, and assist those planning and organizing training programs in IP. The article includes a general part on core curriculum contents, innovative training methods and simulation, and introduces the following articles on the skills that the Interventional Pulmonologist must master in order to perform the different procedures. This monography should be considered a starting point that will evolve over time and results in better training for practitioners and better care for our patients. The task of establishing a trainee's competence to practice independently as an Interventional Pulmonologist remains the responsibility of the IP fellowship program director and faculty, who validate logbooks and assess competence for each procedure. These standards need to be reviewed and approved by national and International Scientific Societies and Healthcare Institutions with the aim to improve, disseminate and incorporate them in healthcare programs.

WormBase is an open-access model-organism database that provides current and accurate genetic information of C. elegans and related nematodes. Users can search WormBase by several fields, including a gene or human disease. A special feature of the database is the inclusion of micropublications, peer-reviewed data that may go unpublished in traditional venues.

The issue of dechelation (transmetallation) in vivo after administration of the linear gadolinium-based contrast agents, and potential safety concerns, is considered on the basis of an extensive, focused literature review. Early indications of potential problems included the high level of excess ligand used in the formulation of 2 agents (indeed the 2 least stable thermodynamically) and interference with laboratory tests when blood was drawn from patients relatively soon after administration of these same agents. The advent of nephrogenic systemic fibrosis in the late 2000s raised additional major concerns.The correlation in 2014 of dentate nucleus hyperintensity on precontrast T1-weighted scans with multiple prior injections of linear gadolinium chelates, in patients with normal renal function, has driven subsequent research concerning dechelation of these agents in vivo. Unexpectedly high levels of gadolinium in the bone, skin, and liver have been found long term after administration, in animal models and in humans, although the latter data are limited. Bone may serve as a long-term reservoir, with a residual excretion phase for gadolinium after intravenous injection of the linear agents due to a subsequent slow release from bone. Many different patient populations could be vulnerable and potentially later develop clinical symptoms, although at this stage there are only limited data and small retrospective uncontrolled studies. Possible vulnerable populations include children, menopausal women, patients with osteoporosis (who are predisposed to fractures and often slow to heal or heal poorly), those receiving multiple doses, those with proinflammatory conditions, moderate renal dysfunction, or an undefined genetic predisposition. Of particular concern would be nephrogenic systemic fibrosis-like symptoms-including particularly pain and skin/joint symptoms, or disease related to the incorporation of gadolinium in hydroxyapatite in bone, in small subgroups of patients with a not yet defined propensity and/or cofactor. These concerns have led to withdrawal of the linear agents from the largest clinical market, Europe, with the exception of the hepatobiliary agents for delayed liver imaging, an indication that cannot be fulfilled by the current macrocyclic gadolinium chelates (for which these concerns do not apply).

Background: Juvenile animal testing has become an established part of drug development to support safe clinical use in the human pediatric population and for eventual drug product label use., Methods and Results: A review of European Paediatric Investigation Plan decisions showed that from 2007 to mid-2017, 229 drugs had juvenile animal work requested, almost exclusively incorporating general toxicology study designs, in rat (57.5%), dog (8%), mouse (4.5%), monkey (4%), pig (2%), sheep (1%), rabbit (1%), hamster (0.5%), and species not specified (21.5%). A range of therapeutic areas were found, but the most common areas were infectious diseases (15%), endocrinology (13.5%), oncology (13%), neurology (11%), and cardiovascular diseases (10%). Examination of major clinical indications within these therapeutic areas showed some level of consistency in the species of choice for testing and the pediatric age that required support. Examination of juvenile animal study findings presented in product labels raises questions around how useful the data are to allow prescribing the drug to a child., Conclusion: It is hopeful that the new ICH S11 guideline "Nonclinical Safety Testing in Support of Development of Pediatric Medicines" currently in preparation will aid drug developers in clarifying the need for juvenile animal studies as well as in promoting a move away from toxicology studies with a conventional design. This would permit more focused testing to examine identified areas of toxicity or safety concerns and clarify the presentation/interpretation of juvenile animal study findings for proper risk assessment by a drug prescriber.

Cell transplantation therapy aspires to repair and restore lost function while minimizing the risk of harm. The potential for harm arises from cell instability, variability, inappropriate behavior, and/or transmission of adventitious pathogens. Quality assured and controlled assessment and production of human cells for clinical use ensures that the risk of harm is minimized. Application of quality standards requires thorough planning and consultation with regulatory authorities on process and product specifications, as early as possible at the research and development (R&D) stage. Here we outline considerations applicable to all human cells in relation to regulatory governance, the route to the clinic and Cell Therapy Product (CTP) characterization, with special emphasis on human pluripotent stem cells (hPSC).

Insight into how genomes change and adapt due to selection addresses key questions in evolutionary biology and in domestication of animals and plants by humans. In that regard, the pig and its close relatives found in Africa and Eurasia represent an excellent group of species that enables studies of the effect of both natural and human-mediated selection on the genome. The recent completion of the draft genome sequence of a domestic pig and the development of next-generation sequencing technology during the past decade have created unprecedented possibilities to address these questions in great detail. In this paper, I review recent whole-genome sequencing studies in the pig and closely-related species that provide insight into the demography, admixture and selection of these species and, in particular, how domestication and subsequent selection of Sus scrofa have shaped the genomes of these animals.

Background: The development of structured and validated training curricula is one of the current priorities in robot-assisted urological surgery., Objective: To establish the feasibility, acceptability, face validity, and educational impact of a structured training curriculum for robot-assisted radical prostatectomy (RARP), and to assess improvements in performance and ability to perform RARP after completion of the curriculum., Design, Setting, and Participants: A 12-wk training curriculum was developed based on an expert panel discussion and used to train ten fellows from major European teaching institutions. The curriculum included: (1) e-learning, (2) 1 wk of structured simulation-based training (virtual reality synthetic, animal, and cadaveric platforms), and (3) supervised modular training for RARP., Outcome Measurements and Statistical Analysis: The feasibility, acceptability, face validity, and educational impact were assessed using quantitative surveys. Improvement in the technical skills of participants over the training period was evaluated using the inbuilt validated assessment metrics on the da Vinci surgical simulator (dVSS). A final RARP performed by fellows on completion of their training was assessed using the Global Evaluative Assessment of Robotic Skills (GEARS) score and generic and procedure-specific scoring criteria., Results and Limitations: The median baseline experience of participants as console surgeon was 4 mo (interquartile range [IQR] 0-6.5 mo). All participants completed the curriculum and were involved in a median of 18 RARPs (IQR 14-36) during modular training. The overall score for dVSS tasks significantly increased over the training period (p<0.001-0.005). At the end of the curriculum, eight fellows (80%) were deemed able by their mentors to perform a RARP independently, safely, and effectively. At assessment of the final RARP, the participants achieved an average score ≥4 (scale 1-5) for all domains using the GEARS scale and an average score >10 (scale 4-16) for all procedural steps using a generic dedicated scoring tool. In performance comparison using this scoring tool, the experts significantly outperformed the fellows (mean score for all steps 13.6 vs 11)., Conclusions: The European robot-assisted urologic training curriculum is acceptable, valid, and effective for training in RARP., Patient Summary: This study shows that a 12-wk structured training program including simulation-based training and mentored training in the operating room allows surgeons with limited robotic experience to increase their robotic skills and their ability to perform the surgical steps of robot-assisted radical prostatectomy., (Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Pharmaceuticals and chemicals are subjected to regulatory safety testing accounting for approximately 25% of laboratory animal use in Europe. This testing meets various objections and has led to the development of a range of 3R models to Replace, Reduce or Refine the animal models. However, these models must overcome many barriers before being accepted for regulatory risk management purposes. This paper describes the barriers and drivers and options to optimize this acceptance process as identified by two expert panels, one on pharmaceuticals and one on chemicals. To untangle the complex acceptance process, the multilevel perspective on technology transitions is applied. This perspective defines influences at the micro-, meso- and macro level which need alignment to induce regulatory acceptance of a 3R model. This paper displays that there are many similar mechanisms within both sectors that prevent 3R models from becoming accepted for regulatory risk assessment and management. Shared barriers include the uncertainty about the value of the new 3R models (micro level), the lack of harmonization of regulatory requirements and acceptance criteria (meso level) and the high levels of risk aversion (macro level). In optimizing the process commitment, communication, cooperation and coordination are identified as critical drivers., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Skeletal muscle ageing is characterized by a progressive and dramatic loss of muscle mass and strength leading to decreased muscular function resulting in muscle weakness which is often referred to as sarcopenia. Following the standardisation of "omics" approaches to study the genome (genomics) and the transcriptome (transcriptomics), the study of the proteins encoded by the genome, referred to as proteomics, is a tremendous challenge. Unlike the genome, the proteome varies in response to many physiological or pathological factors. In addition, the proteome is orders of magnitude more complex than the transcriptome due to post-translational modifications, protein oxidation and limited protein degradation. Proteomic studies, including the analysis of protein abundance as well as post-translational modified proteins have been shown to provide valuable information to unravel the key molecular pathways implicated in complex biological processes, such as tissue and organ ageing. In this article, we will describe proteomic approaches for the analysis of protein abundance as well as the specific protein targets for oxidative damage upon oxidative stress and/or during skeletal muscle ageing.

Xenopus is an essential vertebrate model system for biomedical research that has contributed to important discoveries in many disciplines, including cell biology, molecular biology, physiology, developmental biology, and neurobiology. However, unlike other model systems no central repository/stock center for Xenopus had been established until recently. Similar to mouse, zebrafish, and fly communities, which have established stock centers, Xenopus researchers need to maintain and distribute rapidly growing numbers of inbred, mutant, and transgenic frog strains, along with DNA and protein resources, and individual laboratories struggle to accomplish this efficiently. In the last 5 years, two resource centers were founded to address this need: the European Xenopus Resource Center (EXRC) at the University of Portsmouth in England, and the National Xenopus Resource (NXR) at the Marine Biological Laboratory in Woods Hole, MA. These two centers work together to provide resources and support to the Xenopus research community. The EXRC and NXR serve as stock centers and acquire, produce, maintain and distribute mutant, inbred and transgenic Xenopus laevis and Xenopus tropicalis lines. Independently, the EXRC is a repository for Xenopus cDNAs, fosmids, and antibodies; it also provides oocytes and wild-type frogs within the United Kingdom. The NXR will complement these services by providing research training and promoting intellectual interchange through hosting mini-courses and workshops and offering space for researchers to perform short-term projects at the Marine Biological Laboratory. Together the EXRC and NXR will enable researchers to improve productivity by providing resources and expertise to all levels, from graduate students to experienced PIs. These two centers will also enable investigators that use other animal systems to take advantage of Xenopus' unique experimental features to complement their studies., (Copyright © 2012 Wiley Periodicals, Inc.)

A pediatric assessment is now a required component of every New Drug Application in North America or Marketing Authorization Application in Europe, unless a waiver has been granted previously. Nonclinical juvenile toxicity studies are usually required as part of this assessment. The protocols for juvenile toxicity studies are devised in consultation with the FDA or EMEA. It is important to approach the regulatory authority well in advance in order not to delay the marketing authorization of the drug and to confirm the need or not to perform a preclinical evaluation in juvenile animals. The choice of species and the design of juvenile studies are based on a series of complex considerations, including: the therapeutic use of the drug, the age at which children will be treated, the duration of treatment, and potential age- or species-specific differences in pharmacokinetics or toxicity.

For centuries the function of the spleen was widely debated. Vesalius, while Professor of Anatomy in Padua in the first part of the 16th century, is reported to have removed the spleen in living animals and to have shown that this was consistent with survival. An English surgeon, Timothy Clark reported in 1663 that he had removed the spleen of a stray dog, that the animal lived in good health for a year following this, and was 'subsequently enthusiastic in its pursuit of sexual activity'.

Neuromuscular disorders are a frequent cause of chronic disability in man. They often result from mutations in single genes and are thus, in principle, well suited for gene therapy. However, the tissues involved (muscle and the central nervous system) are post-mitotic, which poses a challenge for most viral vectors. In some cases, alternative approaches may use small molecules, for example, antisense oligonucleotides (AONs). These do not deliver a new gene, but rather modulate existing gene products or alter the utilization of pathways. For Duchenne muscular dystrophy, this approach is in early phase clinical trials, and for two other common neuromuscular disorders (spinal muscular atrophy and myotonic dystrophy), significant preclinical advances have recently been made.

Recognising the crucial role of model organisms in exploring the causes of human disease and in developing safe treatments, the European Commission has invested euro180 million in collaborative research projects on model organisms since 2002. Further financial support is planned for the future. Projects supported by the European Commission are playing an important role in structuring the research landscape in Europe and creating the knowledge base to understand health and disease. Furthermore, they are generating important and freely available data and/or animal resources that will catalyse progress in biomedical research. This paper focuses on animal model organisms and includes the rodents, mouse and rat, other vertebrates such as zebrafish and frog, and also invertebrates such as nematodes. Research on other model organisms, including yeast, bacteria and plants, is also being supported and this is providing knowledge on basic cellular and molecular processes, as well as on host-microorganism interactions.

With the growing cost of using animals to test the safety of new chemicals and an increasing backlog of chemicals awaiting testing, the quest for cell-based in vitro alternatives for toxicity testing is gaining momentum.

Mycobacterium liflandii causes a fatal frog disease in captive anurans. Here we report, to our knowledge, the first epizootic of mycobacteriosis in a European colony of clawed frogs (Silurana tropicalis), previously imported from a United States biologic supply company. Our findings suggest the emerging potential of this infection through international trade.

This paper discusses regulatory requirements essential during the non-clinical development of cancer vaccines. DNA vaccines and vaccines containing monoclonal antibodies are specifically addressed. ICH, CHMP, FDA, and WHO guidance documents in addition to scientific literature are reviewed and the regulatory framework, including respective EMEA and the FDA divisions responsible for review and assessment of cancer vaccines, is described. Selection criteria for an appropriate animal model for efficacy and/or toxicity studies are discussed.

We report the appearance of a Mycoplasma haemocanis infection in laboratory dogs, which has been reported previously, yet, never before in Europe. Outbreak of the disease was triggered by a splenectomy intended to prepare the dogs for a hemorrhagic shock study. The clinical course of the dogs was dramatic including anorexia and hemolytic anemia. Treatment included allogeneic transfusion, prednisone, and oxytetracycline. Systematic follow-up (n = 12, blood smears, antibody testing and specific polymerase chain reaction) gives clear evidence that persistent eradication of M. haemocanis is unlikely. We, therefore, had to abandon the intended shock study. In the absence of effective surveillance and screening for M. haemocanis, the question arises whether it is prudent to continue shock research in splenectomized dogs., (Copyright 2004 S. Karger AG, Basel)

The increased interest and/or need to perform pediatric clinical trials to allow the marketing and safe use of a wider range of medicines in children has raised the profile of the need to conduct juvenile animal studies. It is argued that such studies may identify "unique" toxicities not seen from available adult animal and clinical data. This paper will review the current situation from an industrial, regulatory, and scientific perspective. Areas of important consideration include functional (dynamic) and kinetic differences between children and adults and specific considerations associated with testing in young animals. This paper will also review what are we currently doing? Whether we really need these studies? and What challenges lie in the future?

The European Resource Centre for Alternatives in Higher Education (EURCA: http://www.eurca.org) is an exciting new project, which aims to enable teachers using animals in teaching to be more creative and innovative in their approach to teaching and learning, to foster high-quality training for science students, and to significantly reduce the number of animals used, often unnecessarily, in teaching. This will be achieved by: a) establishing a resource centre--a collection of mainly electronic alternatives, and taking this to relevant scientific meetings in Europe, where it would function as a drop-in advice centre for teachers; b) creating a network of academic teachers who actively use alternatives, to take responsibility for disseminating information about alternatives to other teachers in the European Union, to participate in the activity outlined above, and to share experiences and good practice; c) setting up an Internet website with an expansive, information-rich database (peer-reviews, demos, peer-evaluations, peer-recommendations, links to users, etc.) on selected "tried and tested" alternatives; and d) encouraging and promoting the findings of evaluative studies on the effectiveness of alternatives in higher education teaching and learning.