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)

Validation of the Monitoring Efficacy of Neurogenic Bowel Treatment on Response (MENTOR) Tool in a Japanese Rehabilitation Setting

Study design: Prospective observational study. Objective: To validate the Monitoring Efficacy of NBD Treatment On Response (MENTOR) tool in individuals with a spinal cord injury (SCI) or spina bifida, suffering from neurogenic bowel dysfunction (NBD) in a rehabilitation center in Japan. Methods: First, the MENTOR tool was translated from English to Japanese using a validated translation process. Second, the MENTOR tool was validated in a rehabilitation clinic in Japan. Participants completed the MENTOR tool prior to a consultation with an expert physician. According to the results of the tool, each participant was allocated to one of three categories regarding change in treatment: “adequately treated,” “further discussion,” and “recommended change.” The results of the MENTOR tool were compared with the treatment decision made by an expert physician, who was blinded to the results of the MENTOR tool. Results: A total of 60 participants completed the MENTOR tool. There was an acceptable concordance between individuals allocated as respectively, being adequately treated (100%) and recommended change in treatment (61%) and the physicians’ decision on treatment. The concordance was lower for individuals allocated as requiring further discussion (48%). Conclusions: In this study the MENTOR tool was successfully validated in a Japanese rehab setting. The tool will help identify individuals with SCI that need further treatment of their NBD symptoms

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

How to reach a few percent level in determining the Lense-Thirring effect?

In this paper we discuss and compare a node-only LAGEOS-LAGEOS II combination and a node-only LAGEOS-LAGEOS II-Ajisai-Jason1 combination for the determination of the Lense-Thirring effect. The new combined EIGEN-CG01C Earth gravity model has been adopted. The second combination cancels the first three even zonal harmonics along with their secular variations but introduces the non-gravitational perturbations of Jason1. The first combination is less sensitive to the non-conservative forces but is sensitive to the secular variations of the uncancelled even zonal harmonics of low degree J4 and J6 whose impact grows linearly in time.Comment: Latex2e, 22 pag. 1 table, 2 figures, 45 references. Changes in the Abstract, Introduction and Conclusions. Discussion on the non-gravitational perturbations on Ajisai and on the impact of the secular rates of the even zonal harmonics added. EIGEN-CG01C CHAMP+GRACE+terrestrial gravimetry/altimetry Earth gravity model used. Reference adde

VCAM-1/α4β1 Integrin Interaction is Crucial for Prompt Recruitment of Immune T Cells into the Brain During the Early Stage of Reactivation of Chronic Infection with \u3cem\u3eToxoplasma gondii\u3c/em\u3e to Prevent Toxoplasmic Encephalitis

Reactivation of chronic infection with Toxoplasma gondii can cause life-threatening toxoplasmic encephalitis in immunocompromised individuals. We examined the role of VCAM-1/α4β1 integrin interaction in T cell recruitment to prevent reactivation of the infection in the brain. SCID mice were infected and treated with sulfadiazine to establish a chronic infection. VCAM-1 and ICAM-1 were the endothelial adhesion molecules detected on cerebral vessels of the infected SCID and wild-type animals. Immune T cells from infected wild-type mice were treated with anti-α4 integrin or control antibodies and transferred into infected SCID or nude mice, and the animals received the same antibody every other day. Three days later, sulfadiazine was discontinued to initiate reactivation of infection. Expression of mRNAs for CD3δ, CD4, CD8β, gamma interferon (IFN-γ), and inducible nitric oxide synthase (NOS2) (an effector molecule to inhibit T. gondii growth) and the numbers of CD4+ and CD8+ T cells in the brain were significantly less in mice treated with anti-α4 integrin antibody than in those treated with control antibody at 3 days after sulfadiazine discontinuation. At 6 days after sulfadiazine discontinuation, cerebral tachyzoite-specific SAG1 mRNA levels and numbers of inflammatory foci associated with tachyzoites were markedly greater in anti-α4 integrin antibody-treated than in control antibody-treated animals, even though IFN-γ and NOS2 mRNA levels were higher in the former than in the latter. These results indicate that VCAM-1/α4β1 integrin interaction is crucial for prompt recruitment of immune T cells and induction of IFN-γ-mediated protective immune responses during the early stage of reactivation of chronic T. gondii infection to control tachyzoite growth

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