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Highlights • Late stage failures are decreasing productivity in Pharma R&D. • Endpoints, non-reflective of patient needs, are not met causing late stage failure. • The FDA encourages the use of digital technology to asses patients' needs. • A consortium aims to get regulatory acceptance for real world walking speed. • This collaborative approach will ensure patient centric innovation & endpoints. Digital technologies are transforming healthcare and will provide the basis for more patient-centric innovation in the pharmaceutical industry. Digital endpoints in clinical studies have the potential to drive innovation and reduce costly late-stage failures. This is also currently under consideration by regulatory agencies, such as the US Food and Drug Administration (FDA). The academic–industrial collaboration MOBILISED-D aims to implement and validate real-world walking speed (RWS) as a digital endpoint accepted by regulatory authorities as a first of its class. Previous work has shown that loss of mobility driven by chronic illness and frailty in older patients can be a relevant readout or effect of different diseases and various organ systems. [ABSTRACT FROM AUTHOR]

Abstract: Abnormalities of memory B cells seem to be closely involved in the pathogenesis of primary Sjögrens Syndrome (pSS) and its malignant complication, B cell lymphoma. Recent studies on B cells in pSS add to our understanding of the distinct memory B cell subsets in pSS. Reduction of peripheral memory CD27+ B cells, most strikingly of the CD27+IgM+ subset, may indicate a lack of appropriate censoring mechanisms and incomplete differentiation processes within the ectopic lymphoid tissues in pSS. This ectopically formed lymphoid tissue might protect autoreactive memory B cells from deletion by physiological check-points and, thereby, may contribute to the perpetuation of the disease as well as to an enhanced lymphoma risk. Thus, B cells may be potential targets of direct or indirect treatment in pSS. [Copyright &y& Elsevier]

This review focuses on the use of immunglobulin (Ig) variable region genes by B cells from patients with primary Sjo¨gren's syndrome (pSS) and the biologic insights that this provides. Comparison of the Ig repertoire from the blood and parotid gland of pSS patients with that of normal donors suggests that there are typical disturbances of B cell homeostasis with depletion of memory B cells from the peripheral blood and accumulation/retention of these antigen-experienced B cells in the inflamed tissue. Although there are clonally expanded B cells in the parotid gland, generalized abnormalities in the B cell repertoire are also found in pSS patients. The vast majority of the current data indicate that there is no major molecular abnormality in generating the IgV chain repertoire in patients with pSS. In contrast, disordered selection leads to considerable differences in the VL gene usage and VH CDR3 length of the B cell Ig repertoire in pSS patients. The nature of the influences that lead to disordered selection in pSS remains to be determined, but should provide important clues to the etiology of this autoimmune inflammatory disorder. [Copyright &y& Elsevier]

Despite a considerable growth in space related industry and scientific research over the past few decades, space related education has largely been neglected in our country. NAROM - the National Centre for Space Related Education - was formed last year to organize space related educational activities, to promote recruitment, to promote appreciation for the benefits of space activities, and to stimulate interest for science in general. This year, nine students from Narvik Engineering College have participated in the Hotel Payload Project (HPP) at Andøya Rocket Range. They have thus played an active and essential role in an ongoing engineering project. [Copyright &y& Elsevier]

Cryoablation is one of many local destruction techniques used to remove liver tumors. The procedure is cumbersome and time-consuming if there is no real-time access to intra-operative images as well as navigation information of instruments. In this paper, we propose a software-based solution that addresses issues like interactive, real-time navigation and visualization of cryoprobes, segmented tumor, intra-operative MR images, temperature maps, and isotherm surfaces. The system has an intuitive graphical user interface that provides access to a variety of functionalities. It enables the surgeon to perform the procedure safely, accurately, and rapidly by providing visual decision support mechanism. [Copyright &y& Elsevier]

Biological pacemakers could be a promising alternative to electronic pacemakers and human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM) may represent a suitable source for implantable cells. To further unravel this potential a thorough understanding of pacemaker function with regard to coupling processes both in the physiological and in the graft-host context is required. Here we developed a 2-component cardiac organoid model with a hiPSC-CM embryoid body (EB) as trigger casted into a rat engineered heart tissue (EHT) as arrhythmic beating substrate. Contractility recordings revealed that the EB controlled the beating activity of the EHT, leading to a regular hiPSC-CM-like beating pattern instead of the irregular beating typically seen in rat EHT. Connectivity was observed with action potential (AP) measurements and calcium transients transmitting from the EB directly into the rat EHT. Immunohistochemistry and genetically labeled hiPSC-CMs demonstrated that EB-derived and rat cells intermingled and formed a transitional zone. Connexin 43 expression followed the same pattern as histological and computer models have indicated for the human sinoatrial node. In conclusion, hiPSC-CM EBs function as a biological pacemaker in a 2-component cardiac organoid model, which provides the possibility to study electrophysiological and structural coupling mechanisms underlying propagation of pacemaker activity. [ABSTRACT FROM AUTHOR]

Background: Long noncoding ribonucleic acids (lncRNAs) are a subclass of regulatory noncoding ribonucleic acids for which expression and function in human endothelial cells and angiogenic processes is not well studied.Objectives: The authors discovered hypoxia-sensitive human lncRNAs via next-generation ribonucleic acid sequencing and microarray approaches. To address their functional importance in angiogenic processes, several endothelial lncRNAs were characterized for their angiogenic characteristics in vitro and ex vivo.Methods: Ribonucleic acid sequencing and microarray-derived data showed specific endothelial lncRNA expression changes after hypoxia. Validation experiments confirmed strong hypoxia-dependent activation of 2 intergenic lncRNAs: LINC00323 and MIR503HG.Results: Silencing of these lncRNA transcripts led to angiogenic defects, including repression of growth factor signaling and/or the key endothelial transcription factor GATA2. Endothelial loss of these hypoxia-driven lncRNAs impaired cell-cycle control and inhibited capillary formation. The potential clinical importance of these endothelial lncRNAs to vascular structural integrity was demonstrated in an ex vivo model of human induced pluripotent stem cell-based engineered heart tissue.Conclusions: The authors report an expression atlas of human hypoxia-sensitive lncRNAs and identified 2 lncRNAs with important functions to sustain endothelial cell biology. LncRNAs hold great promise to serve as important future therapeutic targets of cardiovascular disease. [ABSTRACT FROM AUTHOR]

There is ongoing interest in generating cardiomyocytes derived from human induced pluripotent stem cells (hiPSC) to study human cardiac physiology and pathophysiology. Recently we found that norepinephrine-stimulated calcium currents (I Ca) in hiPSC-cardiomyocytes were smaller in conventional monolayers (ML) than in engineered heart tissue (EHT). In order to elucidate culture specific regulation of β 1 -adrenoceptor (β 1 -AR) responses we investigated whether action of phosphodiesterases (PDEs) may limit norepinephrine effects on I Ca and on cytosolic cAMP in hiPSC-cardiomyocytes. Results were compared to adult human atrial cardiomyocytes. Adult human atrial cardiomyocytes were isolated from tissue samples obtained during open heart surgery. All patients were in sinus rhythm. HiPSC-cardiomyocytes were dissociated from ML and EHT. Förster-resonance energy transfer (FRET) was used to monitor cytosolic cAMP (Epac1-camps sensor, transfected by adenovirus). I Ca was recorded by whole-cell patch clamp technique. Cilostamide (300 nM) and rolipram (10 μM) were used to inhibit PDE3 and PDE4, respectively. β 1 -AR were stimulated with the physiological agonist norepinephrine (100 μM). In adult human atrial cardiomyocytes, norepinephrine increased cytosolic cAMP FRET ratio by +13.7 ± 1.5% (n = 10/9, mean ± SEM, number of cells/number patients) and I Ca by +10.4 ± 1.5 pA/pF (n = 15/10). This effect was not further increased in the concomitant presence of rolipram, cilostamide and norepinephrine, indicating saturation by norepinephrine alone. In ML hiPSC-cardiomyocytes, norepinephrine exerted smaller increases in cytosolic cAMP and I Ca (FRET +9.6 ± 0.5% n = 52/21, number of cells/number of ML or EHT, and I Ca + 1.4 ± 0.2 pA/pF n = 34/7, p < 0.05 each) and both were augmented in the presence of the PDE4 inhibitor rolipram (FRET +16.7 ± 0.8% n = 94/26 and I Ca + 5.6 ± 1.4 pA/pF n = 11/5, p < 0.05 each). Cilostamide increased the response to norepinephrine on FRET (+12.7 ± 0.5% n = 91/19, p < 0.05), but not on I Ca. In EHT hiPSC-cardiomyocytes, norepinephrine responses on both, FRET and I Ca , were larger than in ML (FRET +12.1 ± 0.3% n = 87/32 and I Ca + 3.3 ± 0.2 pA/pF n = 13/5, p < 0.05 each). Rolipram augmented the norepinephrine effect on I Ca (+6.2 ± 1.6 pA/pF; p < 0.05 vs. norepinephrine alone, n = 10/4), but not on FRET. Our results show culture-dependent differences in hiPSC-cardiomyocytes. In conventional ML but not in EHT, maximum norepinephrine effects on cytosolic cAMP depend on PDE3 and PDE4, suggesting immaturity when compared to the situation in adult human atrial cardiomyocytes. The smaller I Ca responses to norepinephrine in ML and EHT vs. adult human atrial cardiomyocytes depend at least partially on a non-physiological large impact of PDE4 in hiPSC-cardiomyocytes. • PDE4 exerts at least partially a stronger control of basal and norepinephrine-induced cytosolic cAMP and I Ca in hiPSC-cardiomyocytes. • The unphysiologically large contribution of PDE4 in hiPSC-cardiomyocytes can be a sign of immaturity. • Culture conditions have an impact on the maturation of PDE-mediated regulation of catecholamine action. • Peculiarities of hiPSC-cardiomyocytes should be considered when they are used to analyse catecholamine physiology. [ABSTRACT FROM AUTHOR]