Pre-Going Private Ownership Around the World

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this record.Going private transactions are often highly leveraged, and give rise to potential agency conflicts among existing shareholders. But who exactly are those shareholders, and under what legal conditions are these transaction more likely to occur? We examine ownership structure prior to going private transactions in 33 countries around the world from 2002 to 2014.The data indicate strong and consistent evidence that pre-going private ownership is characterized by higher institutional and corporate ownership. Family ownership lowers the probability of a public to private transaction. Stronger creditor rights increase the probability of going private particularly for whole company and institutional buyout

Pre-going private ownership around the world

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this record Going private transactions are often highly leveraged, and give rise to potential agency conflicts among existing shareholders. But who exactly are those shareholders, and under what legal conditions are these transactions more likely to occur? We examine ownership structure prior to going private transactions in 33 countries around the world from 2002 to 2014. The data indicate strong and consistent evidence that pre-going private ownership is characterized by higher institutional and corporate ownership. Family ownership lowers the probability of a public to private transaction. Stronger creditor rights increase the probability of going private, particularly for whole company and institutional buyouts.Social Sciences and Humanities Research Council of Canad

A Novel Mechanism for Zika Virus Host-Cell Binding

Zika virus (ZIKV) recently emerged in the Western Hemisphere with previously unrecognized or unreported clinical presentations. Here, we identify two putative binding mechanisms of ancestral and emergent ZIKV strains featuring the envelope (E) protein residue asparagine 154 (ASN154) and viral phosphatidylserine (PS). Synthetic peptides representing the region containing ASN154 from strains PRVABC59 (Puerto Rico 2015) and MR_766 (Uganda 1947) were exposed to neuronal cells and fibroblasts to model ZIKV E protein/cell interactions and bound MDCK or Vero cells and primary neurons significantly. Peptides significantly inhibited Vero cell infectivity by ZIKV strains MR_766 and PRVABC59, indicating that this region represents a putative binding mechanism of ancestral African ZIKV strains and emergent Western Hemisphere strains. Pretreatment of ZIKV strains MR_766 and PRVABC59 with the PS-binding protein annexin V significantly inhibited replication of PRVABC59 but not MR_766, suggesting that Western hemisphere strains may additionally be capable of utilizing PS-mediated entry to infect host cells. These data indicate that the region surrounding E protein ASN154 is capable of binding fibroblasts and primary neuronal cells and that PS-mediated entry may be a secondary mechanism for infectivity utilized by Western Hemisphere strains

Drug‐induced shortening of the electromechanical window is an effective biomarker for in silico prediction of clinical risk of arrhythmias

Background and Purpose: Early identification of drug‐induced cardiac adverse events is key in drug development. Human‐based computer models are emerging as an effective approach, complementary to in vitro and animal models. Drug‐induced shortening of the electromechanical window has been associated with increased risk of arrhythmias. This study investigates the potential of a cellular surrogate for the electromechanical window (EMw) for prediction of pro‐arrhythmic cardiotoxicity, and its underlying ionic mechanisms, using human‐based computer models. Experimental Approach: In silico drug trials for 40 reference compounds were performed, testing up to 100‐fold the therapeutic concentrations (EFTPCmax) and using a control population of human ventricular action potential (AP) models, optimised to capture pro‐arrhythmic ionic profiles. EMw was calculated for each model in the population as the difference between AP and Ca2+‐transient durations at 90%. Drug‐induced changes in the EMw and occurrence of repolarisation abnormalities (RA) were quantified. Key Results: Drugs with clinical risk of Torsade de Pointes arrhythmias induced a concentration‐dependent EMw shortening, while safe drugs lead to increase or small change in EMw. Risk predictions based on EMw shortening achieved 90% accuracy at 10x EFTPCmax, whereas RA‐based predictions required 100x EFTPCmax to reach the same accuracy. Due to its dependence on Ca2+‐transient, the EMw was also shown to be more sensitive than AP prolongation in distinguishing between pure hERG blockers and multichannel compounds also blocking the calcium current. Conclusion and Implications: The EMw is an effective biomarker for in silico predictions of drug‐induced clinical pro‐arrhythmic risk, particularly for compounds with multichannel blocking action.</p

Drug‐induced shortening of the electromechanical window is an effective biomarker for in silico prediction of clinical risk of arrhythmias

Background and Purpose: Early identification of drug‐induced cardiac adverse events is key in drug development. Human‐based computer models are emerging as an effective approach, complementary to in vitro and animal models. Drug‐induced shortening of the electromechanical window has been associated with increased risk of arrhythmias. This study investigates the potential of a cellular surrogate for the electromechanical window (EMw) for prediction of pro‐arrhythmic cardiotoxicity, and its underlying ionic mechanisms, using human‐based computer models. Experimental Approach: In silico drug trials for 40 reference compounds were performed, testing up to 100‐fold the therapeutic concentrations (EFTPCmax) and using a control population of human ventricular action potential (AP) models, optimised to capture pro‐arrhythmic ionic profiles. EMw was calculated for each model in the population as the difference between AP and Ca2+‐transient durations at 90%. Drug‐induced changes in the EMw and occurrence of repolarisation abnormalities (RA) were quantified. Key Results: Drugs with clinical risk of Torsade de Pointes arrhythmias induced a concentration‐dependent EMw shortening, while safe drugs lead to increase or small change in EMw. Risk predictions based on EMw shortening achieved 90% accuracy at 10x EFTPCmax, whereas RA‐based predictions required 100x EFTPCmax to reach the same accuracy. Due to its dependence on Ca2+‐transient, the EMw was also shown to be more sensitive than AP prolongation in distinguishing between pure hERG blockers and multichannel compounds also blocking the calcium current. Conclusion and Implications: The EMw is an effective biomarker for in silico predictions of drug‐induced clinical pro‐arrhythmic risk, particularly for compounds with multichannel blocking action.</p

Évaluation de différents isotypes de VEGF 121 dans la réparation vasculaire au cours de la conservation : analyse dans un modèle pré-clinique

International audienceObjectifsLe réseau vasculaire est reconnu comme une cible majeure au cours de l’ischémie reperfusion avec les conséquences à cours et long terme sur le devenir des organes. Il a été démontré que l’évolution péjorative de fonction des reins peut être liée à réponse discordante entre hypoxia inducible factor-1α (HIF-1α) et vascular endothelial growth factor (VEGF). Dans cette perspective, nous avons étudié différents isotypes de VEGF.MéthodesDeux isotypes de VEGF (165 et 121) ont été étudiés après ajout dans la solution Viaspan (UW solution) à la posologie de 25 μg par litre de solution de conservation. L’évaluation s’est faite dans un modèle d’autotransplantation rénale chez le porc Large White (6 animaux par groupe) avec un suivi à 3 mois et comparée à un groupe témoin et un groupe néphrectomisé. La reprise de fonction rénale et la réaction inflammatoire (détermination des marqueurs pro inflammatoires) et les marqueurs de lésions tubulaires. À trois mois, les animaux étaient sacrifiés. L’expression de HIF-1α ; VEGF et TGF-β et l’évaluation de la fibrose tubulo-interstitielle étaient effectuées.RésultatsAprès 24 h de conservation, la reprise de fonction s’est faite plus précocement dans le groupe conservé avec Viaspan + VEGF 121 et durant le suivi des animaux (Fig. 1). Les fonctions tubulaires ont également été significativement améliorées. Au niveau tissulaire, le tenuer en eau était moins importante avec le groupe Viaspan + VEGF 121. L’utilisation du VEGF 121 a limité l’expression des marqueurs pro-inflammatoire de façon significative pour TNF-α, Il-1 et HMGB1 (Fig. 2). L’excrétion urinaire et la détermination plasmatique de NGAL est diminuée significativement dans les deux groupes traités mais de façon plus marquée dans le groupe traité avec VEGF 121. Trois mois après la transplantation, la fibrose interstitielle et l’atrophie tubulaire étaient réduites de façon plus marquée dans le groupe Viaspan + VEGF 121 (Tableau 1).ConclusionCe travail l’importance des facteurs intervenant sur les lésions vasculaires et leur intérêt dans la réparation. De plus, le type de la molécule concernée est important avec un impact différent en fonction des isotypes. Ce travail souligne que la cellule endothéliale est une cible qui mérite une approche thérapeutique conjuguée et complémentaire, pouvant avoir des conséquences sur l’aspect tubulaire

Combining an in silico proarrhythmic risk assay with a tPKPD model to predict QTc interval prolongation in the anesthetized guinea pig assay

Human-based in silico models are emerging as important tools to study the effects of integrating inward and outward ion channel currents to predict clinical proarrhythmic risk. The aims of this study were 2-fold: 1) Evaluate the capacity of an in silico model to predict QTc interval prolongation in the in vivo anesthetized cardiovascular guinea pig (CVGP) assay for new chemical entities (NCEs) and; 2) Determine if a translational pharmacokinetic/pharmacodynamic (tPKPD) model can improve the predictive capacity. In silico simulations for NCEs were performed using a population of human ventricular action potential (AP) models. PatchXpress® (PX) or high throughput screening (HTS) ion channel data from respectively n = 73 and n = 51 NCEs were used as inputs for the in silico population. These NCEs were also tested in the CVGP (n = 73). An M5 pruned decision tree-based regression tPKPD model was used to evaluate the concentration at which an NCE is liable to prolong the QTc interval in the CVGP. In silico results successfully predicted the QTc interval prolongation outcome observed in the CVGP with an accuracy/specificity of 85%/73% and 75%/77%, when using PX and HTS ion channel data, respectively. Considering the tPKPD predicted concentration resulting in QTc prolongation (EC5%) increased accuracy/specificity to 97%/95% using PX and 88%/97% when using HTS. Our results support that human-based in silico simulations in combination with tPKPD modeling can provide correlative results with a commonly used early in vivo safety assay, suggesting a path toward more rapid NCE assessment with reduced resources, cycle time, and animal use