Translational medicine: science or wishful thinking?

"Translational medicine" as a fashionable term is being increasingly used to describe the wish of biomedical researchers to ultimately help patients. Despite increased efforts and investments into R&D, the output of novel medicines has been declining dramatically over the past years. Improvement of translation is thought to become a remedy as one of the reasons for this widening gap between input and output is the difficult transition between preclinical ("basic") and clinical stages in the R&D process. Animal experiments, test tube analyses and early human trials do simply not reflect the patient situation well enough to reliably predict efficacy and safety of a novel compound or device. This goal, however, can only be achieved if the translational processes are scientifically backed up by robust methods some of which still need to be developed. This mainly relates to biomarker development and predictivity assessment, biostatistical methods, smart and accelerated early human study designs and decision algorithms among other features. It is therefore claimed that a new science needs to be developed called 'translational science in medicine'

Translatability score revisited: differentiation for distinct disease areas

Background: Translational science supports successful transition of early biomedical research into human applications. In 2009 a translatability score to assess risk and identify strengths and weaknesses of a given project has been designed and successfully tested in case studies. The score elements, in particular the contributing weight factors, are heterogeneous for different disease areas; therefore, the score was individualized for six areas (cardiovascular, oncology, psychiatric, anti-viral, anti-bacterial/fungal and monogenetic diseases). Results: FDA reviews and related literature were used for modifications of the score with emphasis on biomarkers, personalized medicine and animal models. 113 new medical entities approved by FDA from 2012 through 2016 were evaluated and metrics obtained for companion diagnostics and animal models as starting points for author-based individualization of the score. Most drugs approved in this period were related to oncology (46%), while the approvals were lowest for psychiatrics (4%). The evaluation of the FDA package inserts revealed that companion diagnostics play an important role in every field except psychiatrics. Further the analysis of the FDA reviews showed the weakness of animal models in psychiatrics and anti-virals, while useful animal models were present for all other fields. Consequently the scoring system was adapted to the different fields, resulting in increased weights for animal models, biomarker and personalized medicine in oncology. For psychiatrics the weights for animal models, biomarker and personalized medicine were decreased, while the weight for model compounds, clinical trials and surrogate or endpoint strategy were increased. For anti-viral drugs weights for in vitro data and personalized medicine were increased, while the weight for animal models was decreased. Further, for anti-bacterial/fungal drugs weights for animal models and personalized medicine were increased. Weights were increased for genetics and personalized medicine and decreased for model compounds for monogenetic orphans. Conclusions: Adaptation of the score to different disease areas should help to support a structured and diverse approach to translation and encourage researchers in the private or public sectors to further customize the score

Translatability scoring in drug development: eight case studies

Translational medicine describes the transfer of basic in vitro and in vivo data into human applications. In the light of low rates of market approvals for new medical entities, better strategies to predict the risk of drug development should be used to increase output and reduce costs. Recently, a scoring system to assess the translatability of early drug projects has been proposed. Here eight drugs from different therapeutic areas have been subjected to a retrospective test-run in this system fictively located at the phase II-III transition. The scores gained here underline the importance of biomarker quality which is pivotal to decrease the risk of the project in all cases. This is particularly evident for gefitinib. The EGFR mutation status is a breakthrough biomarker to predict therapeutic success which made this compound clinically acceptable, and this is plausibly reflected by a considerable increase of the translatability score. For psychiatric and Alzheimer's drugs, and for a CETP-inhibitor, the lack of suitable biomarkers and animal models is reflected by a low translatability score, well correlating with the excessive translational risk in these areas. These case studies document the apparent utility of the scoring system, at least under retrospective conditions, as the scores correlate with the outcomes at the level of market approval. Prospective validation is still missing, but these case studies are encouraging

Nongenomic effects of aldosterone on phosphocreatine levels in human calf muscle during recovery from exercise.

Nongenomic in vitro effects of aldosterone on the sodium-proton antiport and intracellular second messengers have been described in human mononuclear leukocytes, vascular smooth muscle cells, and endothelial cells. To test the potential physiological relevance of these effects, an in vivo 31P magnetic resonance spectroscopy study on the human calf at rest and during exercise was performed in 10 healthy volunteers receiving either 1 mg aldosterone or placebo iv in a double blind, randomized, cross-over trial. Spectra were analyzed for phosphocreatine, ATP, phosphomonoesters, inorganic intracellular phosphate, and intracellular pH. Resting values remained unchanged by aldosterone. After isometric contraction of the calf (50% body weight for 3 min), phosphocreatine recovered to significantly higher levels after application of aldosterone compared with placebo. Other parameters were not significantly changed by aldosterone. Effects appeared immediately after isometric contraction and, thus, occurred within 8 min of aldosterone administration. They are, therefore, likely to represent the first contemporary evidence of nongenomic in vivo effects of aldosterone in man. These findings also point to an involvement of aldosteron in the acute stress adaptation of cellular oxidative metabolism in human muscle physiology

The Inositol- 1,4,5=Trisphosphate System Is Involved in Rapid Effects of Aldosterone in Human Mononuclear Leukocytes

There is increasing evidence for rapid steroid action on electrolyte transport in human mononuclear leukocytes (HML). In HML, aldosterone stimulates the Na+/H+ antiporter within a few minutes. Because a variety of hormones and growth factors activate the Na+/H+ antiporter via protein kinase C and inositol phospholipids, a possible involvement of inositol-1,4,5-trisphosphate (IP3) in the rapid effects of aldosterone in HML was investigated. The stimulation of IP3 generation was started by the addition of aldosterone, concanavalin A, or other steroids. A significant increase in IP3 levels by aldosterone (1 nmol/L, P < 0.05) was found after 1 min, similar to that found after concanavalin A (25 micrograms/mL). Aldosterone caused a concentration-dependent elevation of IP3 levels, with an apparent EC50 of approximately 0.1 nmol/L. Fludrocortisone stimulated IP3 generation at similar concentrations, whereas a weaker IP3 stimulation by glucocorticoids (hydrocortisone, dexamethasone) occurred at micromolar concentrations only. Canrenone, a potent inhibitor of classical aldosterone action, was not effective up to a concentration of 100 nmol/L. These findings show kinetic and pharmacological similarities with both the functional data on Na+/H+ antiport stimulation by aldosterone and the studies of 125I-aldosterone binding to plasma membranes of HML. Thus, these data are the first to indicate an involvement of the phosphoinositide pathway in the rapid membrane effects of aldosterone

Towards Reducing the Complexity of Enterprise Architectures by Identifying Standard Variants Using Variability Mining

For decades, Enterprise Architectures (EAs) of car manufacturers have been constantly evolved to respond to growing requirements. As a consequence, EAs have often reached a very high level of complexity, which leads to problems in adapting EAs to new environmental condi­tions. Such a new condition is, for instance, digitalization of society (e.g., social media, Internet of Things) which has a huge effect on the automotive industry and the grown EA. Resulting changes in complex EAs have long implementation cycles, require enormous communica­tion efforts, and lead to high development costs. To alle­viate these problems, in this paper, we present a concept to reduce the complexity of grown EAs by adapting the Family Mining approach. This approach is originally used to compare block-oriented models, such as MATLAB/Si­mulink models, and to identify commonalities and diffe­rences between these models. In our concept, we utilize the Family Mining approach to analyze the variability of a particular EA and to identify the contained variants. All information about the variability and the variants will be used to derive standard variants representing default so­lutions for different issues. Using these standard variants, the existing EA will be restructured involving economic considerations (e.g., which standard variant yields best benefits under certain circumstances). Hence, applying this concept to a complex EA should allow reducing the complexity of the EA, alleviating related problems and making suitable design decisions for future extensions

Aldosterone rapidly activates Src kinase in M-1 cells involving the mineralocorticoid receptor and HSP84

AbstractWe investigated the effect of aldosterone on Src kinase. In the kidney cell line, M-1 aldosterone leads to a >2-fold transient activation of Src kinase seen as early as 2 min after aldosterone administration. Maximal Src kinase activation was measured at an aldosterone concentration of 1 nM. In parallel to activation, autophosphorylation at Tyr-416 of Src kinase increased. Src kinase activation was blocked by spironolactone. Aldosterone led to increased association of Src with HSP84. Furthermore, rapamycin blocked aldosterone-induced Src activation. We conclude that Src activation by aldosterone is mediated through the mineralocorticoid receptor and HSP84

Appropriateness of oral anticoagulants for long-term treatment of atrial fibrillation in older people: results of an evidence-based review and international consensus validation process (OAC-FORTA 2016)

Background: Age appropriateness of anticoagulants for stroke prevention in atrial fibrillation is uncertain. Objective: To review oral anticoagulants for the treatment of atrial fibrillation in older (age >65 years) people and to classify appropriate and inappropriate drugs based on efficacy, safety and tolerability using the Fit-fOR-The-Aged (FORTA) classification. Methods: We performed a structured comprehensive review of controlled clinical trials and summaries of individual product characteristics to assess study and total patient numbers, quality of major outcome data and data of geriatric relevance. The resulting evidence was discussed in a round table with an interdisciplinary panel of ten European experts. Decisions on age appropriateness were made using a Delphi process. Results: For the eight drugs included, 380 citations were identified. The primary outcome results were reported in 32 clinical trials with explicit and relevant data on older people. Though over 24,000 patients aged >75/80 years were studied for warfarin, data on geriatric syndromes were rare (two studies reporting on frailty/falls/mental status) and missing for all other compounds. Apixaban was rated FORTA-A (highly beneficial). Other non-vitamin K antagonist oral anticoagulants (including low/high-intensity dabigatran and high-intensity edoxaban) and warfarin were assigned to FORTA-B (beneficial). Phenprocoumon, acenocoumarol and fluindione were rated FORTA-C (questionable), mainly reflecting the absence of data. Conclusions: All non-vitamin K antagonist oral anticoagulants and warfarin were classified as beneficial or very beneficial in older persons (FORTA-A or -B), underlining the overall positive assessment of the risk/benefit ratio for these drugs. For other vitamin-K antagonists regionally used in Europe, the lack of evidence should challenge current practice

Position paper: Rapid responses to steroids: current status and future prospects.

Steroids exert their actions through several pathways. The classical genomic pathway, which involves binding of steroids to receptors and subsequent modulation of gene expression, is well characterized. Besides this, rapid actions of steroids have been shown to exist. Since 30 years, research on rapid actions of steroids is an emerging field of science. Today, rapid effects of steroids are well established, and are shown to exist for every type of steroid. The classical steroid receptors have been shown to be involved in rapid actions, but there is also strong evidence that unrelated structures mediate these rapid effects. Despite increasing knowledge about the mechanisms and structures which mediate these actions, there is still no unanimous acceptance of this category. This article briefly reviews the history of the field including current controversies and challenges. It is not meant as a broad review of literature, but should increase the awareness of the endocrinology society for rapid responses to steroids. As members of the organizing committee of the VI International Meeting on Rapid Responses to Steroid Hormones 2009, we propose a research agenda focusing on the identification of new receptoral structures and the identification of mechanisms of actions at physiological steroid concentrations. Additionally, efforts for the propagation of translational studies, which should finally lead to clinical benefit in the area of rapid steroid action research, should be intensified