Cell therapy has proven to be a burgeoning field of investigation, evidenced by hundreds of clinical trials being conducted worldwide across a variety of cell types and indications. Many cell ...therapies have been shown to be efficacious in humans, such as modified T-cells and natural killer (NK) cells. Adoptive immunotherapy has shown the most promise in recent years, with particular emphasis on autologous cell sources. Chimeric Antigen Receptor (CAR)-based T-cell therapy targeting CD19-expressing B-cell leukemias has shown remarkable efficacy and reproducibility in numerous clinical trials. Recent marketing approval of Novartis' Kymriah™ (tisagenlecleucel) and Gilead/Kite's Yescarta™ (axicabtagene ciloleucel) by the FDA further underscores both the promise and legwork to be done if manufacturing processes are to become widely accessible. Further work is needed to standardize, automate, close, and scale production to bring down costs and democratize these and other cell therapies. Given the multiple processing steps involved, commercial-scale manufacturing of these therapies necessitates tighter control over process parameters. This focused review highlights some of the most recent advances used in the manufacturing of therapeutic immune cells, with a focus on T-cells. We summarize key unit operations and pain points around current manufacturing solutions. We also review emerging technologies, approaches and reagents used in cell isolation, activation, transduction, expansion, in-process analytics, harvest, cryopreservation and thaw, and conclude with a forward-look at future directions in the manufacture of adoptive immunotherapies.
ABSTRACT
The renminbi is currently undergoing a process of internationalization which has raised fundamental questions about the evolution of the international monetary system and the dominance of ...the US dollar. In this article, we assess how far the renminbi has travelled down the internationalization road and analyse the possibilities for it challenging the role of the US dollar in the future. We utilize Cohen's () taxonomy to document the current dimensions of renminbi internationalization. Looking forward, we briefly summarize three common approaches to analysing currency internationalization, and propose a new approach. We argue that renminbi internationalization should be seen as a response to crises, first the Asian financial crisis and then the global financial crisis. As such, we argue that current internationalization has been driven by short‐term problem solving rather than a coherent long‐term strategy. The current path of RMB internationalization is best described as one of ‘currency normalization’ rather than ‘currency dominance’.
The northwest region of British Columbia, Canada has been at the center of multiple fossil fuel projects over the past decade as corporations have sought access to the coastline in order to export ...their products. Analyzing the dynamics of how and why groups and communities responded to two specific fossil fuel projects, we address the question: why did the "unlikely alliance" formed at the local level in northwest B.C. to resist the Enbridge oil pipeline project fracture just a few years later in the case of the LNG Canada/Coastal GasLink Liquefied Natural Gas project and pipeline project? We argue that the fracturing arose in part because of historic vulnerabilities of the resource periphery, and the legacy of settler colonial governance but also because state and corporate actors used their powers to increase the financial incentives for communities to support LNG projects, to change the discourse on fossil fuels by promoting the concept of LNG as "clean"energy, deflecting attention from the fracking of natural gas, and to isolate environmental organizations by casting them as "outsiders." The findings contribute to the literature by analyzing the reasons not only for the formation but also for the fragility and fracturing of alliances in contemporary energy politics.
The developmental state is an important concept within critical development studies. This article examines two questions. The first is how the developmental state has been impacted by globalization ...processes. This is traced for five globalization processes: the globalization of finance, of production, and of trade, global climate change and global class structures. The second issue examined is how, through the prism of the developmental state, critical development studies intersects, fuses, and diverges from globalization studies. The answers to both questions are shown to be complex and difficult but not without interesting insights and possibilities.
In the present study, the potential synergism between beneficial lactic acid bacteria (Pediococcus acidilactici) contained in a probiotic and a mixture of fermentable complex carbohydrates and ...autolyzed brewer’s yeast (or prebiotic) were explored in red drum. Four experimental diets were formulated from practical ingredients, and the basal diet was supplemented with either probiotic, prebiotic, or both supplements. Red drum juveniles (~5.5 g) were offered the four experimental diets for 56 days, and at the end of the feeding trial fish fed diets supplemented with probiotic had significantly better weight gain than those fed the non-supplemented diets, and higher protein content in their whole-body composition. Transient intestinal microbiome alpha and beta diversity were significantly affected by the dietary treatments. Interestingly, a higher relative abundance of the lactic acid genus Pediococcus was observed for fish fed diets supplemented with the prebiotic. A higher relative abundance was also observed for the predicted functions of the microbial metagenome, and many of these pathways involved the biosynthesis of essential amino acids, vitamins, and nucleotides. Even though no potential synergistic effect was observed, the individual inclusion of these prebiotic and probiotic supplements positively affected the intestinal health and growth performance of red drum, respectively.
•Genetic deletion of mutant KRAS enhances the antigen presentation pathway.•Intracellular antibody targeting of mutant KRAS increases MHC class I expression.•Mutant KRAS alters expression of the ...NKG2D ligand ULBP2.•Mutant KRAS does not alter susceptibility to NK cells.
Mutations in the RAS family of oncogenes are highly prevalent in human cancer and, amongst its manifold effects, oncogenic RAS impairs the expression of components of the antigen presentation pathway. This allows evasion of cytotoxic T lymphocytes (CTL). CTL and natural killer (NK) cells are reciprocally regulated by MHC class I molecules and any gain in CTL recognition obtained by therapeutic inactivation of oncogenic RAS may be offset by reduced NK cell activation. We have investigated the consequences of targeted inactivation of oncogenic RAS on the recognition by both CTL and NK cells. Inactivation of oncogenic RAS, either by genetic deletion or inactivation with an inducible intracellular domain antibody (iDAb), increased MHC class I expression in human colorectal cell lines. The common RAS mutations, at codons 12, 13 and 61, all inhibited antigen presentation. Although MHC class I modulates the activity of both CTL and NK cells, the enhanced MHC class I expression resulting from inactivation of mutant KRAS did not significantly affect the in vitro recognition of these cell lines by either class of cytotoxic lymphocyte. These results show that oncogenic RAS and its downstream signalling pathways modulate the antigen presentation pathway and that this inhibition is reversible. However, the magnitude of these effects was not sufficient to alter the in vitro recognition of tumour cell lines by either CTL or NK cells.
The social licence to operate is a concept that has been applied to the mining sector internationally for the past two decades. In 2017, it was raised by a number of actors as a way to reduce ...controversy over mining projects in Greenland. In this paper, we analyse why the concept of social licence appeared, and the legitimacy problems that it was intended to resolve despite numerous changes to Greenland’s mining approval processes. We argue that the concept was introduced primarily as a way of seeking to enhance the voices and agency of local communities in resource governance. We further ask whether, on the basis of Canadian experience where social licence has been used for much longer in natural resource governance discourse, introducing the concept into Greenland will likely lead to an empowerment of communities. We argue that the Canadian experience in this regard shows that the outcome is complex, that community empowerment can take different forms or may not occur at all. Such complexity is also likely in Greenland.
Le permis social d’exploitation est un concept qui a cours dans le secteur minier international depuis deux décennies. En 2017, ce permis social a été soulevé par un certain nombre d’acteurs comme manière d’atténuer la controverse entourant les projets miniers du Groenland. Dans cet article, nous analysons ce qui a donné le jour au permis social d’exploitation et les problèmes de légitimité que ces permis étaient censés résoudre malgré les nombreux changements apportés aux processus d’approbation de l’exploitation minière au Groenland. Nous soutenons que le concept a été principalement adopté pour tenter d’améliorer la voix et l’instrumentalité des communautés locales en matière de gouvernance des ressources. Par ailleurs, nous tâchons de déterminer, en fonction de l’expérience canadienne où le permis social d’exploitation est utilisé depuis beaucoup plus longtemps dans le discours de la gouvernance des ressources naturelles, si l’adoption de ce concept au Groenland engendrera vraisemblablement l’autonomisation des communautés. Nous soutenons que l’expérience canadienne à cet égard montre que le résultat est complexe, que l’autonomisation des communautés peut prendre différences formes, ou qu’elle peut ne pas se concrétiser du tout. Une telle complexité est également susceptible de survenir au Groenland.
A practical synthesis of SGLT2 inhibitor candidate ertugliflozin (1) has been developed for potential commercial application. The highly telescoped process involves only three intermediate isolations ...over a 12-step sequence. The dioxa-bicyclo3.2.1octane motif is prepared from commercially available 2,3,4,6-tetra-O-benzyl-d-glucose, with nucleophilic hydroxymethylation of a 5-ketogluconamide intermediate as a key step. The aglycone moiety is introduced via aryl anion addition to a methylpiperazine amide. High chemical purity of the API is assured through isolation of the crystalline penultimate intermediate, tetraacetate 39. A cocrystalline complex of the amorphous solid 1 with l-pyroglutamic acid has been prepared in order to improve the physical properties for manufacture and to ensure robust API quality.
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