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.
In the nineteenth century there flourished a peculiar breed of Englishmen—often the second sons of the aristocracy, or ambitious men from a lower class—who as soldiers, consuls and tea planters, were ...largely responsible for making England a great colonial power.Save for the fact that he is a staunch anticolonialist, Paul Bowles resembles these men in many respects. Like them, he appears to be happiest away from civilization as we know it; like them, he thrives when the traveling is hardest, the food ghastly or infrequent, water scarce, heat intolerable, or mosquitoes abundant.This engaging collection of eight travel essays by the author of such noted fiction as The Sheltering Sky and The Delicate Prey deals largely with places in the world that few Westerners have ever heard of, much less seen—places as yet unencumbered by the trappings, luxuries, and corruptions of modern civilization. Except for one essay on Central America, all of these pieces are concerned with remote spots in the Hindu, Buddhist, or Mohammedan worlds. The author is a sympathetic and discerning interpreter of these alien cultures, and his eyes and ears are especially alert both to what is bizarre and what is wise in the civilizations in which he settles. He is also acutely aware of the transitions occurring on the fringes of many of these regions, and he is disturbed and indignant about the corrosive effect of Western culture on the non-Christian way of life.Above all, however, Paul Bowles is a superb and observant traveler—born wanderer who finds pleasure in the inaccessible and who cheerfully endures the concomitant hardships matter-of-factly and with humor.These essays provide us with Paul Bowles's characteristic insightfulness and bring us closer to a world we frequently hear about, but often find difficult to understand.
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.
Volatile organic compound (VOC) emissions were measured from Chinese Hamster Ovary (CHO) cell and T cell bioreactor gas exhaust lines with the goal of non-invasively metabolically profiling the ...expansion process. Measurements of cellular 'breath' were made directly from the gas exhaust lines using polydimethylsiloxane (PDMS)-coated magnetic stir bars, which underwent subsequent thermal desorption-gas chromatography-mass spectrometry (TD-GC-MS) analysis. Baseline VOC profiles were observed from bioreactors filled with only liquid media. After inoculation, unique VOC profiles correlated to cell expansion over the course of 8 d. Partial least squares (PLS) regression models were built to predict cell culture density based on VOC profiles of CHO and T cells (R
= 0.671 and R
= 0.769, respectively, based on a validation data set). T cell runs resulted in 47 compounds relevant to expansion while CHO cell runs resulted in 45 compounds; the 20 most relevant compounds of each cell type were putatively identified. On the final experimental days, sorbent-covered stir bars were placed directly into cell-inoculated media and into media controls. Liquid-based measurements from spent media containing cells could be distinguished from media-only controls, indicating soluble VOCs excreted by the cells during expansion. A PLS-discriminate analysis (PLS-DA) was performed, and 96 compounds differed between T cell-inoculated media and media controls with 72 compounds for CHO cells; the 20 most relevant compounds of each cell line were putatively identified. This work demonstrates that the volatilome of cell cultures can be exploited by chemical detectors in bioreactor gas and liquid waste lines to non-invasively monitor cellular health and could possibly be used to optimize cell expansion conditions 'on-the-fly' with appropriate control loop systems. Although the basis for statistical models included compounds without certain identification, this work provides a foundation for future research of bioreactor emissions. Future studies must move towards identifying relevant compounds for understanding of underlying biochemistry.
Opposition to mines endures even in countries with relatively strong environmental assessment processes and regulations. Why proposed mines fail to obtain a social license to operate is analyzed by ...developing a framework comprised of three concepts—process legitimacy, distributional outcomes, and values compatibility—drawing from the social license to operate, interactive governance, and environmental justice literatures. The framework is applied to understand opposition from local Indigenous people to two mine projects, one in Sweden and the other in British Columbia, Canada. Evidence from interviews with Sami legal experts and Reindeer Herding Community representatives and an advisor with the Tŝilhqot’in National Government, as well as from secondary sources is used to analyze the contestation. Despite the proposed mines being situated in different governance contexts, the reasons for the opposition are markedly similar - environmental assessment processes are illegitimate, distributional outcomes unfair, and values incompatible. The comparative empirical analysis leads to refining the framework as a scaffold with values compatibility as the foundational plank, rather than three independent planks contributing to a social license to operate. The analysis offers insights into company commitments to Indigenous engagement, enhancements to process legitimacy, and evolving and paradigmatic shifts in governance processes, as articulated by Indigenous peoples and international governance mechanisms such as the 2007 United Nations
Declaration on the Rights of Indigenous Peoples
.
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