Possible Contexts of Use for In Silico trials methodologies: a consensus- based review

The term In Silico Trial indicates the use of computer modelling and simulation to evaluate the safety and efficacy of a medical product, whether a drug, a medical device, a diagnostic product or an advanced therapy medicinal product. Predictive models are positioned as new methodologies for the development and the regulatory evaluation of medical products. New methodologies are qualified by regulators such as FDA and EMA through formal processes, where a first step is the definition of the Context of Use (CoU), which is a concise description of how the new methodology is intended to be used in the development and regulatory assessment process. As In Silico Trials are a disruptively innovative class of new methodologies, it is important to have a list of possible CoUs highlighting potential applications for the development of the relative regulatory science. This review paper presents the result of a consensus process that took place in the InSilicoWorld Community of Practice, an online forum for experts in in silico medicine. The experts involved identified 46 descriptions of possible CoUs which were organised into a candidate taxonomy of nine CoU categories. Examples of 31 CoUs were identified in the available literature; the remaining 15 should, for now, be considered speculative

Mechanical strain stimulates COPII‐dependent secretory trafficking via Rac1

Cells are constantly exposed to various chemical and physical stimuli. While much has been learned about the biochemical factors that regulate secretory trafficking from the endoplasmic reticulum (ER), much less is known about whether and how this trafficking is subject to regulation by mechanical signals. Here, we show that subjecting cells to mechanical strain both induces the formation of ER exit sites (ERES) and accelerates ER‐to‐Golgi trafficking. We found that cells with impaired ERES function were less capable of expanding their surface area when placed under mechanical stress and were more prone to develop plasma membrane defects when subjected to stretching. Thus, coupling of ERES function to mechanotransduction appears to confer resistance of cells to mechanical stress. Furthermore, we show that the coupling of mechanotransduction to ERES formation was mediated via a previously unappreciated ER‐localized pool of the small GTPase Rac1. Mechanistically, we show that Rac1 interacts with the small GTPase Sar1 to drive budding of COPII carriers and stimulates ER‐to‐Golgi transport. This interaction therefore represents an unprecedented link between mechanical strain and export from the ER

Loop Quantum Cosmology: A Status Report

The goal of this article is to provide an overview of the current state of the art in loop quantum cosmology for three sets of audiences: young researchers interested in entering this area; the quantum gravity community in general; and, cosmologists who wish to apply loop quantum cosmology to probe modifications in the standard paradigm of the early universe. An effort has been made to streamline the material so that, as described at the end of section I, each of these communities can read only the sections they are most interested in, without a loss of continuity.Comment: 138 pages, 15 figures. Invited Topical Review, To appear in Classical and Quantum Gravity. Typos corrected, clarifications and references adde

Identification of heat shock protein 32 (Hsp32) as a novel target in acute lymphoblastic leukemia

Heat shock proteins (Hsp) are increasingly employed as therapeutic targets in oncology. We have shown that Hsp32, also known as heme oxygenase-1 (HO-1), serves as survival factor and potential target in Ph+ chronic myeloid leukemia. We here report that primary cells and cell lines derived from patients with acute lymphoblastic leukemia (ALL) express Hsp32 mRNA and the Hsp32 protein in a constitutive manner. Highly enriched CD34+/CD38- ALL stem cells also expressed Hsp32. Two Hsp32-targeting drugs, pegylated zinc protoporphyrine (PEG-ZnPP) and styrene maleic acid-micelle-encapsulated ZnPP (SMA-ZnPP), induced apoptosis and growth arrest in the BCR/ABL1+ cell lines, in Ph- lymphoblastic cell lines and in primary Ph+ and Ph- ALL cells. The effects of PEG-ZnPP and SMA-ZnPP on growth of leukemic cells were dose-dependent. In Ph+ ALL, major growth-inhibitory effects of the Hsp32-targeting drugs were observed in imatinib-sensitive and imatinib-resistant cells. Hsp32-targeting drugs were found to synergize with imatinib, nilotinib, and bendamustine in producing growth inhibition and apoptosis in Ph+ ALL cells. A siRNA against Hsp32 was found to inhibit growth and survival of ALL cells and to synergize with imatinib in suppressing the growth of ALL cells. In conclusion, Hsp32 is an essential survival factor and potential new target in ALL.Sabine Cerny-Reiterer, Renata A. Meyer, Harald Herrmann, Barbara Peter, Karoline V. Gleixner, Gabriele Stefanzl, Emir Hadzijusufovic, Winfried F. Pickl, Wolfgang R. Sperr, Junia V. Melo, Hiroshi Maeda, Ulrich Jäger, Peter Valen

A target-disease network model of second-generation BCR-ABL inhibitor action in Ph+ ALL

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is in part driven by the tyrosine kinase bcr-abl, but imatinib does not produce long-term remission. Therefore, second-generation ABL inhibitors are currently in clinical investigation. Considering different target specificities and the pronounced genetic heterogeneity of Ph+ ALL, which contributes to the aggressiveness of the disease, drug candidates should be evaluated with regard to their effects on the entire Ph+ ALL-specific signaling network. Here, we applied an integrated experimental and computational approach that allowed us to estimate the differential impact of the bcr-abl inhibitors nilotinib, dasatinib, Bosutinib and Bafetinib. First, we determined drug-protein interactions in Ph+ ALL cell lines by chemical proteomics. We then mapped those interactions along with known genetic lesions onto public protein-protein interactions. Computation of global scores through correlation of target affinity, network topology, and distance to disease-relevant nodes assigned the highest impact to dasatinib, which was subsequently confirmed by proliferation assays. In future, combination of patient-specific genomic information with detailed drug target knowledge and network-based computational analysis should allow for an accurate and individualized prediction of therapy.Uwe Rix, a, Jacques Colinge, Katharina Blatt, Manuela Gridling, Lily L. Remsing Rix, a, Katja Parapatics, Sabine Cerny-Reiterer, Thomas R. Burkard, Ulrich Jäger, Junia V. Melo, Keiryn L. Bennett, Peter Valent, Giulio Superti-Furg

Psychological Well-Being of Parents of Very Young Children With Type 1 Diabetes – Baseline Assessment

Background: Type 1 diabetes in young children is a heavy parental burden. As part of pilot phase of the KIDSAP01 study, we conducted a baseline assessment in parents to study the association between hypoglycemia fear, parental well-being and child behavior. Methods: All parents were invited to fill in baseline questionnaires: hypoglycemia fear survey (HFS), WHO-5, Epworth Sleepiness Scale and Strength and Difficulties Questionnaire (SDQ). Results: 24 children (median age: 5-year, range 1-7 years, 63% male, mean diabetes duration: 3 ± 1.7 years) participated. 23/24 parents filled out the questionnaires. We found a higher score for the hypoglycemia fear behavior 33.9 ± 5.6 compared to hypoglycemia worry 34.6 ± 12.2. Median WHO-5 score was 16 (8 - 22) with poor well-being in two parents. Median daytime sleepiness score was high in five parents (>10). For six children a high total behavioral difficulty score (>16) was reported. Pro social behavior score was lower than normal in six children (<6). Parental well-being was negatively associated with HFS total (r = - 0.50, p <.05) and subscale scores (r = - 0.44, p <.05 for HFS-Worry and HFS-Behavior), child behavior (r = - 0.45, p = .05) and positively with child age and diabetes duration (r = 0.58, p <.01, r = 0.6, p <.01). HFS, parental well-being nor daytime sleepiness are associated with the HbA1c. Conclusion: Regular screening of parental well-being, hypoglycemia fear and child behavior should be part of routine care to target early intervention

Functional brain outcomes of L2 speech learning emerge during sensorimotor transformation

Sensorimotor transformation (ST) may be a critical process in mapping perceived speech input onto non-native (L2) phonemes, in support of subsequent speech production. Yet, little is known concerning the role of ST with respect to L2 speech, particularly where learned L2 phones (e.g., vowels) must be produced in more complex lexical contexts (e.g., multi-syllabic words). Here, we charted the behavioral and neural outcomes of producing trained L2 vowels at word level, using a speech imitation paradigm and functional MRI. We asked whether participants would be able to faithfully imitate trained L2 vowels when they occurred in non-words of varying complexity (one or three syllables). Moreover, we related individual differences in imitation success during training to BOLD activation during ST (i.e., pre-imitation listening), and during later imitation. We predicted that superior temporal and peri-Sylvian speech regions would show increased activation as a function of item complexity and non-nativeness of vowels, during ST. We further anticipated that pre-scan acoustic learning performance would predict BOLD activation for non-native (vs. native) speech during ST and imitation. We found individual differences in imitation success for training on the non-native vowel tokens in isolation; these were preserved in a subsequent task, during imitation of mono- and trisyllabic words containing those vowels. fMRI data revealed a widespread network involved in ST, modulated by both vowel nativeness and utterance complexity: superior temporal activation increased monotonically with complexity, showing greater activation for non-native than native vowels when presented in isolation and in trisyllables, but not in monosyllables. Individual differences analyses showed that learning versus lack of improvement on the non-native vowel during pre-scan training predicted increased ST activation for non-native compared with native items, at insular cortex, pre-SMA/SMA, and cerebellum. Our results hold implications for the importance of ST as a process underlying successful imitation of non-native speech