Co-evolutionary and systemic study on the evolution of emerging stem cell-based therapies

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this record.Newly emerging therapeutic technologies have the potential to reconfigure the understanding, diagnosis, and treatment of diseases, and, consequently, to impact human health. This study integrates co-evolutionary and system-oriented perspectives to investigate factors influencing the way emerging therapies evolve in their attempt to become established medical practices. We examined the case of the use of induced pluripotent stem (iPS) cellbased therapies for age-related macular degeneration (AMD) disease. Cell therapy evolution is explored by considering their constitutive components, namely disease, biomedical technologies, and clinical practices, and observing the changes experienced by their underlying knowledge structures. We adopted a mixed methods approach that simultaneously uses publication, patent, and clinical trial data. Our results highlight the significance of the diversity of technological possibilities, the role of subjective issues in the selection of directions of search, the complementary nature between established and emerging therapies, and the tight product-process interdependencies. This study contributes to an understanding of the difficulties encountered during the emergence of new cell therapies, and the ways in which such difficulties can be circumvented to establish effective and safe cell-based clinical practices.This work was financially supported by MEXT/JSPS World Premier International Research Center (WPI) Initiative [AAR] and by MEXT/JSPS Kakenhi Grant No. 26301022 [SS] and MEXT/JSPS Kakenhi Grant No. 16K17165 [AAR]. Funding is also provided by Organisation in Transition Research Cluster, University of Exeter Business School, University of Exeter, UK (No. 1-SC-C-N68-242-USC01-SSC31-A355-PZSC177)

Cost-Effectiveness Analysis of Transanal Irrigation for Managing Neurogenic Bowel Dysfunction in Japan.

BACKGROUND: Neurogenic bowel dysfunction (NBD) is a common sequela in Spinal Cord Injury (SCI) patients. Bowel dysfunction symptoms have a significant negative impact on quality of life (QOL) and are often socially disabling. Transanal irrigation (TAI) is a bowel management procedure that significantly mitigates NBD symptoms in patients refractory to standard bowel care (SBC) by reducing the incidence of fecal incontinence, ameliorating constipation, and improving QOL. TAI devices are used across many countries such as the United Kingdom, Germany, and France, and introduction of the devices is being considered in Japan. In this context, a cost-effectiveness analysis specific to Japanese settings is relevant. OBJECTIVES: To analyze the cost-effectiveness of TAI for bowel management of SCI patients with NBD in a Japanese clinical setting. Methods: A modified version of a previously developed and published Markov model was used to evaluate the cost-effectiveness of TAI. In the model, SCI patients using TAI due to NBD were compared with SCI patients not responding to TAI and continuing with SBC. Quality-adjusted Life Years (QALYs) were used as the primary effectiveness measure, and the analysis was conducted from the payer's perspective. RESULTS: The model predicts a lifetime incremental cost of TAI to be 3 198 687 yen compared with SBC. TAI provided an additional 0.8 QALY, which leads to an incremental cost-effectiveness ratio (ICER) of TAI vs SBC of 4 016 287 yen/QALY. CONCLUSIONS: An ICER of 4 million yen falls within the range of reported willingness to pay (WTP) per QALY gain (5-6.7 million yen) in Japan, and TAI is therefore found to be a cost-effective treatment strategy compared to SBC. The result should be further corroborated in future Japanese trials of TAI

Performance of V-4Cr-4Ti Alloy Exposed to the JFT-2M Tokamak Environment

A long-term test has been conducted in the JFT-2M tokamak fusion device to determine the effects of environmental exposure on the mechanical and chemical behavior of a V-4Cr-4Ti alloy. Test specimens of the alloy were exposed in the outward lower divertor chamber of JFT-2M in a region away from direct contact with the plasma and were preheated to 300 C just prior to and during selected plasma discharges. During their nine-month residence time in JFT-2M, the specimens experienced approximately 200 lower single-null divertor shots at 300 C, during which high energy particle fluxes to the preheated test specimens were significant, and approximately 2,010 upper single-null divertor shots and non-diverter shots at room temperature, for which high energy particle fluxes to and expected particle retention in the test specimens were very low. Data from post-exposure tests have indicated that the performance of the V-4Cr-4Ti alloy would not be significantly affected by environmental exposure to gaseous species at partial pressures typical for tokamak operation. Deuterium retention in the exposed alloy was also low (<2 ppm). Absorption of interstitial by the alloy was limited to the very near surface, and neither the strength nor the Charpy impact properties of the alloy appeared to be significantly changed from the exposure to the JFT-2M tokamak environment

Ribosomal oxygenases are structurally conserved from prokaryotes to humans

2-Oxoglutarate (2OG)-dependent oxygenases have important roles in the regulation of gene expression via demethylation of N-methylated chromatin components1,2 and in the hydroxylation of transcription factors3 and splicing factor proteins4. Recently, 2OG-dependent oxygenases that catalyse hydroxylation of transfer RNA5,6,7 and ribosomal proteins8 have been shown to be important in translation relating to cellular growth, TH17-cell differentiation and translational accuracy9,10,11,12. The finding that ribosomal oxygenases (ROXs) occur in organisms ranging from prokaryotes to humans8 raises questions as to their structural and evolutionary relationships. In Escherichia coli, YcfD catalyses arginine hydroxylation in the ribosomal protein L16; in humans, MYC-induced nuclear antigen (MINA53; also known as MINA) and nucleolar protein 66 (NO66) catalyse histidine hydroxylation in the ribosomal proteins RPL27A and RPL8, respectively. The functional assignments of ROXs open therapeutic possibilities via either ROX inhibition or targeting of differentially modified ribosomes. Despite differences in the residue and protein selectivities of prokaryotic and eukaryotic ROXs, comparison of the crystal structures of E. coli YcfD and Rhodothermus marinus YcfD with those of human MINA53 and NO66 reveals highly conserved folds and novel dimerization modes defining a new structural subfamily of 2OG-dependent oxygenases. ROX structures with and without their substrates support their functional assignments as hydroxylases but not demethylases, and reveal how the subfamily has evolved to catalyse the hydroxylation of different residue side chains of ribosomal proteins. Comparison of ROX crystal structures with those of other JmjC-domain-containing hydroxylases, including the hypoxia-inducible factor asparaginyl hydroxylase FIH and histone Nε-methyl lysine demethylases, identifies branch points in 2OG-dependent oxygenase evolution and distinguishes between JmjC-containing hydroxylases and demethylases catalysing modifications of translational and transcriptional machinery. The structures reveal that new protein hydroxylation activities can evolve by changing the coordination position from which the iron-bound substrate-oxidizing species reacts. This coordination flexibility has probably contributed to the evolution of the wide range of reactions catalysed by oxygenases

Psychological attachment to the group: Cross-cultural differences in organizational identification and subjective norms as predictors of workers' turnover intentions

Two studies wed the theory of reasoned action, social identity theory, and Ashforth and Mael's work on organizational identification to predict turnover intentions in Japanese and British commercial and academic organizations. In both studies and in both countries, the authors expected and found that identification with the organization substantially and significantly predicted turnover intentions. Attitudes predicted intentions only in Study 2, and subjective norms significantly predicted intentions across both studies. The authors hypothesized that subjective norms would be a significantly stronger predictor of turnover intentions in a collectivist setting. This prediction was supported. Although social identity is strongly associated with turnover intentions across both cultures, the subjective normative aspects of group membership are significantly more strongly associated in the Japanese organizations