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Seclen Luna, Jean Pierre, e Pablo Moya Fernández. "Exploring the relationship between KIBS co-location and the innovativeness of the manufacturing firms in Latin America". Investigaciones Regionales - Journal of Regional Reserach 48 (19 de outubro de 2020): 16. http://dx.doi.org/10.38191/iirr-jorr.20.021.
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Literature has provided empirical evidence showing the importance of location for understanding KIBS effective service provision. According to territorial servitization postulates KIBS are also fundamental for the development of the manufacturing firms. Despite KIBS can be an important source of innovation, limited attention is paid of KIBS in Latin America region. The purpose of this research is analysing the relationship between KIBS co-location and innovativeness of the manufacturing firms. Drawing on the World Bank Enterprise Survey 2017 for Latin-American countries, authors analyse 3,029 manufacturing firms using OLS method. Findings indicate that manufacturing firms’ location based on KIBS proximity is a critical determinant of innovativeness. This relationship is considerably stronger in Central American countries, where according to our data there is KIBS scarcity.
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Pelletier, Louis. "An experiment in ?historically correct? Canadian photoplays: Montreal's British American Film Manufacturing Co." Film History: An International Journal 19, n.º 1 (março de 2007): 34–48. http://dx.doi.org/10.2979/fil.2007.19.1.34.
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Sun Jae Won. "Pioneering Action for American Welfare Capitalism: Founder’s Challenge at the N. O. Nelson Manufacturing Co., 1886~1918". Review of Business History 32, n.º 4 (dezembro de 2017): 209–22. http://dx.doi.org/10.22629/kabh.2017.32.4.009.
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Dawson, Patrick. "Australian technology meets American manufacturing: A case study of industrial collaboration". Human Factors and Ergonomics in Manufacturing 8, n.º 2 (1998): 111–23. http://dx.doi.org/10.1002/(sici)1520-6564(199821)8:2<111::aid-hfm2>3.0.co;2-6.
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GODLEY, ANDREW, MARRISA JOSEPH e DAVID LESLIE-HUGHES. "Technology Transfer in the Interwar U.S. Pharmaceutical Sector: The Case of E. Merck of Darmstadt and Merck & Co., Rahway, New Jersey". Enterprise & Society 20, n.º 3 (7 de junho de 2019): 613–51. http://dx.doi.org/10.1017/eso.2018.97.
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This is a case study of the U.S. pharmaceutical producer, Merck & Co. By 1940 this was one of the leading pharmaceutical producers in the United States, and the company went on to become one of the global industry leaders after World War II. It was founded in 1891 as the U.S. subsidiary of a much larger German pharmaceutical company, E. Merck of Darmstadt. The existing understanding of Merck & Co.’s history emphasizes how it was reacquired by the American branch of the Merck family after wartime sequestration, and from then onward it pursued a path of development separate from its former parent. This article revisits that history of the company and shows how the two Mercks began to cooperate and share technology and manufacturing know-how during the 1930s, something that was particularly to the advantage of Merck & Co.
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Matsumura, Takashi, e Norikazu Suzuki. "Special Issue on Recent Advanced Manufacturing Science and Technology". International Journal of Automation Technology 18, n.º 4 (5 de julho de 2024): 461–62. http://dx.doi.org/10.20965/ijat.2024.p0461.
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Recently, manufacturing technologies have progressed owing to high industrial demand. For example, in the automobile and aircraft industries, manufacturing processes require technologies that allow for high machining rates of lightweight and/or difficult-to-cut materials. Fabricating medical equipment involves the machining of biocompatible materials with high mechanical strength. Information devices require high-quality ultraprecision manufacturing processes. Furthermore, measurement and characterization technologies are also essential for manufacturing. Along with the evolution of manufacturing technologies, scientific studies have been performed on manufacturing phenomena and process control based on physical and/or mathematical aspects. This special issue was promoted by the International Conference on Leading Edge Manufacturing/Materials & Processing (LEM&P2023) held from June 12, 2023 to June 16, 2023 at Rutgers University in New Brunswick, sponsored by the Japan Society of Mechanical Engineers. This conference was co-located with the Manufacturing Science Engineering Conference (MSEC), ASME, and North American Manufacturing Research Conference (NAMRC), SME. This special issue includes nine papers that describe the innovations and detailed progress in the following areas: - Characterization of materials - Fundamental study and modeling of material removal process - Manufacturing control and optimization - Manufacturing processes for new hard materials - Micro-/Nano-scale manufacturing - Tool manufacturing and performance - Metrology and evaluation - Surface characterization This special issue includes technical and scientific discussions that suggest new key technologies for future manufacturing. We hope that this will help readers understand manufacturing processes and improve their operations. We thank the authors and reviewers for their generous cooperation and the editing staff for their contributions.
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Hem-Lee-Forsyth, Shivaughn, Bibiana Sandoval e Hanna Bryant. "A tridimensional view of the Hispanic Health Paradox: Its relationship with faith, the enclave theory, and familism". Advances in Social Sciences Research Journal 8, n.º 12 (31 de dezembro de 2021): 317–45. http://dx.doi.org/10.14738/assrj.812.11476.
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This paper examines the "Hispanic (American) Health Paradox," the juxtaposition of Hispanics’ longer lifespan than the average American amid numerous inequities regarding social determinants of health. Hispanic Americans endure multiple health disparities with a higher incidence and prevalence of chronic conditions. They also experience multiple psychosocial and physical health challenges, including higher rates of food insecurity, poverty, segregation, discrimination, and limited or no access to medical care. Nevertheless, Hispanics enjoy better physical well-being and lower mortality rates when compared to non-Hispanics in the United States (Ruiz et al., 2021). This project aims to analyze the sources of this group’s biosocial advantages and resilience, allowing them to have a longer lifespan amidst their lower health status and increased risk for chronic conditions. It explores the political and social justice implications of these inequities. It also examines the strategies to close the gap on Latinos' current health care disparities via public policy aspects of federal and state legislature. A narrative review method was utilized to examine the existing literature on this paradoxical effect. Keywords based on Medical Subject Headings (MeSH) used to search resources for relevant studies included: Hispanic health paradox (health paradox, immigrant paradox), ethnic minorities (Latinos, LatinX), health disparities (disproportionate health, health inequities), social justice (healthcare stakeholders, health inequities solutions, inequities recommendations), mental health, physical health, and co-morbidities. A quality assessment of full-text peer-reviewed articles yielded 80 articles to compile this narrative review. The research revealed that, despite glaring disparities in social determinants of health, Hispanic Americans have overall experienced better health outcomes through a culture that emphasizes spirituality, community support, and strong family ties.
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DAWSON, ANDREW. "Reassessing Henry Carey (1793–1879): The Problems of Writing Political Economy in Nineteenth-Century America". Journal of American Studies 34, n.º 3 (dezembro de 2000): 465–85. http://dx.doi.org/10.1017/s0021875851006358.
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In April 1859 a group of well-to-do manufacturers and Republican politicians coaxed a reclusive Henry Carey, Philadelphia's pre-eminent economist, from his study to a public dinner in his honour. One hundred and twenty five names were at the foot of an invitation to dine at the opulent La Pierre Hotel in recognition of Carey's “service in behalf of American industrial interests.” The banqueting hall glittered with brilliantly illuminated chandeliers trimmed with floral arrangements; at one end a banner proclaimed “Protection to American Labor,” although, curiously, none of the guests looked as though they actually laboured; strung across the other end of the hall another banner blazoned “Harmony of Interests,” but only one interest sat at table. These two slogans encapsulate Carey's world view. He had a vision of an ideal America in which small manufacturing towns would spread across the land. To him “association ” allowed farmers to exchange products with neighbouring mechanics and to develop America beyond the stage of primary producer. Towns would grow into cities, generate a social and cultural life, and cities would trade with other cities. By such a process all underdeveloped nations would achieve economic maturity. Through the free association of co-operating individuals, town and country and capital and labour achieved harmony. The only way to overcome the baneful effect of British imperialism was through the protective tariff. To Carey's way of thinking, free trade was the antithesis of association because it created “centralization,” a system in which a core industrial capitalism traded manufactures for raw materials with a faraway and less developed periphery. Trading at such a distance allowed a merchant class to intervene and siphon off the hard-won efforts of labour. Free trade led to wild, speculative fluctuations in economic activity, periodic overproduction as consumers were not matched by producers, and long-term underdevelopment of the agricultural regions of the American South and West which lay outside the orbit of north-eastern manufacturers. Carey's ripened theoretical position was consequent upon the enormous changes experienced by American society during the decades of the 1830s, 40s and 50s. Like all utopias, the future was intimately linked to the hopes and fears of the present. To the growing but still subaltern class of manufacturers that rubbed shoulders at La Pierre's dinner tables, he offered a comforting vision of American small-town life as an antidote to the reality of British social polarization and class conflict.
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Larkin, Patrick S. "Job Satisfaction in Public Horticulture". HortScience 30, n.º 4 (julho de 1995): 902B—902. http://dx.doi.org/10.21273/hortsci.30.4.902b.
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Much has been written about how job satisfaction may or may not affect production, morale, and quality of work. However, most job satisfaction studies have been conducted in the area of manufacturing and management, but none have been conducted in the field of public horticulture. Job satisfaction was examined in 245 employees from 30 public horticulture institutions in the mid-Atlantic region of the American Association of Botanic Gardens and Arboreta (AABGA) using the Job Descriptive Index (JDI) and Job in General (JIG). Our purpose was to determine if differences in job satisfaction existed based on an individual' s job (management, horticulture, or other), sex, or other demographic information. In general, public horticulture employees reported satisfaction with work on their current job, supervision of co-workers, and their jobs in general, but showed dissatisfaction with their opportunities for promotion. They were ambivalent about their current pay. However, significant differences (P < 0.05) were seen between the sexes on satisfaction with current pay and among management, horticulture, and other staff on work on current job, current pay, opportunities for promotion, and co-workers.
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Nowak, Ireneusz, Adriana Nowak e Aleksandra Leska. "Zgnilec amerykański jako choroba zakaźna pszczół miodnych – wybrane aspekty prawno-środowiskowe". Studia Prawno-Ekonomiczne 115 (29 de setembro de 2020): 87–107. http://dx.doi.org/10.26485/10.26485/spe/2020/115/5.
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Przedmiot badań: Publikacja dotyczy problematyki związanej ze zwalczaniem choroby zakaźnej pszczół miodnych (Apis mellifera), jaką jest zgnilec amerykański (Paenibacillus larvae, American foulbrood, zgnilec złośliwy), w świetle polskich unormowań prawnych. Przedstawione rozważania obejmują co do zasady ustawę z dnia 11 marca 2004 r. o ochronie zdrowia zwierząt oraz zwalczaniu chorób zakaźnych zwierząt, a także rozporządzenie Ministra Rolnictwa i Rozwoju Wsi z dnia 11 lipca 2016 r. w sprawie zwalczania zgnilca amerykańskiego pszczół oraz Kodeks dobrej praktyki produkcyjnej w pszczelarstwie jako regulację niemającą mocy wiążącej. Ponadto przedmiotem artykułu jest także wykazanie roli pszczół w całym ekosystemie wraz z danymi statystycznymi prezentującymi m.in. liczbę pszczelarzy i pni pszczelich w Polsce za lata 2009–2018 oraz liczbę ognisk zgnilca amerykańskiego w Polsce w latach 2012–2018.1
Cel badawczy: Teza badawcza zmierza do udzielenia odpowiedzi na podstawowe pytanie –czy rozwiązania przyjęte w polskim prawodawstwie w wystarczający sposób chronią populacjępszczoły miodnej przed zagrożeniem w postaci zgnilca amerykańskiego. Metoda badawcza: W publikacji zastosowano formalno-dogmatyczną analizę tekstu prawnego z perspektywy nauk biologicznych i weterynaryjnych. W tym celu wykorzystano w opracowaniu także informacje uzyskane z Ministerstwa Rolnictwa i Rozwoju Wsi, Ministerstwa Środowiska, Instytutu Ogrodnictwa – Zakładu Pszczelnictwa w Puławach, a także raporty pokontrolne Najwyższej Izby Kontroli.
Wyniki: Zdaniem Autorów polskie regulacje prawne w zakresie zwalczania zgnilca amerykańskiego należy co do zasady ocenić pozytywnie, choćby z uwagi na fakt, że jako jedyne schorzenie zakaźne pszczół miodnych na terytorium Rzeczypospolitej Polskiej nieprzerwanie od 1946 r. podlega z urzędu obowiązkowemu zwalczaniu. Nie oznacza to jednak, że nie dostrzeżono żadnych mankamentów w analizowanych unormowaniach prawnych. Takim przykładem jest chociażby brak ustawowego obowiązku rejestracji założonych pasiek w weterynaryjnych jednostkach organizacyjnych przez wszystkie podmioty utrzymujące pszczoły wraz informowaniem o każdej zmianie stanu prawnego lub faktycznego związanego z prowadzoną działalnością.
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Datta, Dipayan, S. G. Ramesh Kumar, M. B. Aswath Narayanan, A. Leena Selvamary e A. Sujatha. "Emerging market of tobacco". International Journal Of Community Medicine And Public Health 5, n.º 6 (22 de maio de 2018): 2161. http://dx.doi.org/10.18203/2394-6040.ijcmph20182140.
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Tobacco industry throughout the world started growing larger and larger. Large firms like British American Tobacco, Imperial Tobacco, China National Tobacco Co. etc. have been manufacturing and exporting tremendous amount of tobacco products. But concurrent research works were also growing to investigate the ill impact of tobacco on health and environment. Since the mid-1960s, strong evidence of the lethal effects of tobacco consumption has led to a sharp decline in official support for producers and manufacturers of tobacco. As the industry is struggling with reduction in smoking rates, huge sales taxes and strict regulations in mature markets, developing economies are offering the emerging markets with better prospects. Ideally, interventions that specifically address a market failure should be implemented as the “best” options. As part of moving towards a more sustainable form of globalization, a global enabling environment linked to local actions should focus on the following strategies: global information management; development of nationally and locally grounded action; global regulation, legal instruments, and foreign policy; and establishment of strong partnerships with purpose.
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Womack, Gabby C. "Racial Passing off the Record: A Journey in Reconnection and Navigating Shifting Identities". Genealogy 6, n.º 1 (18 de janeiro de 2022): 8. http://dx.doi.org/10.3390/genealogy6010008.
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Anyone of African descent or with African ancestry who engages in a genealogy project soon learns that the U.S. Census is a helpful yet frustrating tool. In 2016, equipped with my history degree and an online ancestry search engine, I searched for my great-grandfather Leroy in census records after I saw a picture of him as a young man at work in Philadelphia. This image would have been unremarkable had it not been for the fact that my African American ancestor was so light skinned that he seemed to blend in with his co-workers at Kramer’s Fruit and Vegetables. I thought there had to be a story behind this. Classified as, “Mu”, for mulatto in most of his records, Leroy became “Black” on the census in 1930. My first thought was to question whether this categorization changed for other folks like him. My research led me to my master’s thesis “From ‘Mulatto’ to ‘Negro’: How Fears of ‘Passing’ Changed the 1930 United States Census”. Through this research, I also became closer to my father’s family. This piece will take you through this journey of discovery and my frustrations along the way.
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Sriwangrach, Bunyawat. "A Contrastive Corpus-based Study of American and English Adjectives: ‘Important’ and ‘Significant’". Shanlax International Journal of Education 12, n.º 2 (1 de março de 2024): 32–44. http://dx.doi.org/10.34293/education.v12i2.7227.
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This contrastive corpus-based study aims to analyze the similarities and differences of two synonyms “important” and “significant” concerning on the degree of formality in their distribution across genres as well as their collocations and semantic preference. The corpus data derived from the Corpus of Contemporary American English (COCA) and the British National Corpus (BNC) which represent varieties of English usage across different cultures (American and British). This study analyzed the top 20 noun collocates with Mutual Information (MI) scores value of at least three. The corpus data from COCA and BNC explored some shared characteristics and contrastive features. The findings discovered that the two adjectives have the same core meaning and degree of formality since their highest frequency in academic texts whereas frequencies are the lowest in informal genres i.e. TV and movie subtitles and fiction. In certain conditions, these synonyms are different in terms of noun collocation due to the fact that these synonyms co-occur with particular noun collocates. Interestingly, the findings also confirm two adjectives are near synonyms as they share only two similar theme of semantic preference. In consequence, the two synonyms cannot be used interchangeably in all contexts. Moreover, it was found that the corpora provide some useful details that are deficient in the dictionary.
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Zenere, Giorgio, Carol Poortman, Afreen Sayed, Devi Gunasekera, Cheryl Bolinger, Pooja Chauhan, Jacques Plummer et al. "Abstract 1791: Next generation UltraCAR-T® cells with intrinsic checkpoint inhibition and overnight manufacturing overcome suppressive tumor microenvironment leading to sustained antitumor activity". Cancer Research 83, n.º 7_Supplement (4 de abril de 2023): 1791. http://dx.doi.org/10.1158/1538-7445.am2023-1791.
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Abstract The UltraCAR-T® platform, with decentralized overnight manufacturing, has shifted the autologous CAR-T manufacturing paradigm. This disruptive approach has been validated in clinical and pre-clinical studies for both hematologic and solid tumors. UltraCAR-T cells, manufactured using an overnight process with minimal ex vivo manipulation of autologous T cells. UltraCAR-T cells are engineered to co-express CAR, membrane bound IL-15, and kill switch genes using non-viral gene transfer via high-throughput UltraPorator™ system. Multigenic design and overnight manufacturing renders UltraCAR-T cells with enhanced in vivo expansion and persistence for durable antitumor activity. Chronic antigen stimulation from the tumor can lead to CAR T having an exhausted phenotype contributing to treatment failures. Next generation UltraCAR-T cells also incorporate a novel cell intrinsic blockade of PD-1, superseding the need for combination therapy with checkpoint inhibitors and mitigate classic T cell exhaustion that occurs from chronic stimulation, thereby expanding the therapeutic window for efficacy. Using mesothelin (MSLN) as an exemplar from the CAR-target library, we developed a robust in vitro and in vivo model of continuous tumor antigen exposure to evaluate antitumor activity of the UltraCAR-T cells. MSLN UltraCAR-T cells were generated with and without intrinsic PD-1 blockade. In vitro, UltraCAR-T cells with intrinsic PD-1 blockade demonstrated enhanced inflammatory cytokine expression and cytotoxicity at low effector:target ratios. In long-term co-culture assays with recurring challenge of MSLN+ PD-L1+ tumor cells every 2-3 days, UltraCAR-T cells with intrinsic PD-1 blockade showed sustained potent cytotoxicity which was superior to CAR-T cells lacking PD-1 blockade and in combination with αPD-1 antibody. Intrinsic PD-1 blockade markedly enhanced polyfunctionality of UltraCAR-T cells in the presence of MSLN+ PD-L1+ tumor. In xenograft solid tumor model, a single administration of MSLN UltraCAR-T cells manufactured using UltraPorator demonstrated significant antitumor efficacy. Blood analysis showed sustained downregulation of PD-1, robust antigen specific expansion and durable persistence with central memory/stem-cell memory as the dominant phenotype of UltraCAR-T in vivo. Rechallenging the mice, who became tumor-free after a single UltraCAR-T infusion, with tumor for a second time to simulate tumor relapse led to the significant reduction in tumor burden without additional UltraCAR-T treatment. Collectively, these pre-clinical data highlight the improved efficacy of intrinsic PD-1 blockade in next generation UltraCAR-T cells using non-viral gene delivery and an established rapid, decentralized manufacturing process. Citation Format: Giorgio Zenere, Carol Poortman, Afreen Sayed, Devi Gunasekera, Cheryl Bolinger, Pooja Chauhan, Jacques Plummer, Shamim Ahmad, Rutul R. Shah, Helen Sabzevari, Douglas E. Brough, Tim Chan. Next generation UltraCAR-T® cells with intrinsic checkpoint inhibition and overnight manufacturing overcome suppressive tumor microenvironment leading to sustained antitumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1791.
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Whitmal, Ayana. "Deriving a complex <em>BIN</em> through adverbial <em>BIN</em> complexes". Proceedings of the Linguistic Society of America 7, n.º 1 (5 de maio de 2022): 5288. http://dx.doi.org/10.3765/plsa.v7i1.5288.
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Work by Green (1998) discusses 3 sub-types of stressed BIN in African American English (AAE): stative, habitual, and completive. BIN constructions that co-occur with temporal adverbials exhibit limited grammaticality, with each sub-type differing in how they interact with these adverbials. Non-BIN constructions that involve multiple instances in the same clause of adverbials of the same class exhibit restrictions that resemble BIN + adverbial data. Drawing on works that analyze BIN as a remote past marker (Rickford 1975, Green 1998) and on works connecting adverbial position to interpretation (Ernst 2020), I argue that BIN is an adverbial itself that situates the initiation of an eventuality in the remote past. This adverbial BIN, in concert with certain combinations of tense and aspect, forms a complex that makes up the canonical BIN construction.
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Chan, Tim, Cheryl Bolinger, Sean Scott, Mengyan Du, Carol Poortman, Byron Koenitzer, Taranjit Athwal et al. "Abstract 2821: Incorporation of intrinsic checkpoint blockade enhances functionality of multigenic autologous UltraCAR-T® cells manufactured using non-viral gene delivery and rapid manufacturing process". Cancer Research 82, n.º 12_Supplement (15 de junho de 2022): 2821. http://dx.doi.org/10.1158/1538-7445.am2022-2821.
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Abstract Current chimeric antigen receptor (CAR)-T manufacturing utilizes viral vectors and extensive ex vivo expansion at large central facilities leading to an exhausted CAR-T phenotype, high costs and long vein-to-vein times. While allogeneic CAR-T can reduce delays in patient treatment, they require extensive manipulation of donor cells, severe lymphodepletion and demonstrate short persistence limiting their therapeutic window. The UltraCAR-T® platform is designed to overcome these limitations by utilizing non-viral multigene delivery and a rapid, decentralized manufacturing process without ex vivo activation or expansion of T cells. Patient’s own T cells are collected and manufactured at the medical center and re-infused one day after gene transfer. Here we describe the next generation UltraCAR-T platform that addresses the inhibitory tumor microenvironment by incorporating a novel mechanism for intrinsic downregulation of one or more checkpoint inhibitor (CPI) genes. Our design achieves intrinsic CPI blockade without gene editing and is aimed at avoiding systemic toxicity and the high cost of combining CPI antibodies. Next generation UltraCAR-T cells simultaneously express CAR, membrane bound IL-15 (mbIL15), kill switch, and incorporate intrinsic CPI blockade. To illustrate the ability of this platform, we designed exemplary non-viral transposons to generate UltraCAR-T cells against multiple tumor targets incorporating intrinsic blockade of either one (PD-1) or two (PD-1 and TIGIT) CPI genes. Healthy donor T cells were transfected using the UltraPorator™ electroporation system to manufacture UltraCAR-T cells without ex vivo activation or expansion. The co-expression of CAR, mbIL15 and kill switch was confirmed by flow cytometry and western blot. Activated UltraCAR-T showed significant reduction in CPI gene expression compared to control CAR-T cells lacking the CPI blockade and did not show unintended off-target activity. Downregulation of CPI gene(s) on UltraCAR-T enhanced cytotoxicity and inflammatory cytokine production, especially at low effector to target (E:T) cell ratios, when co-cultured with PD-L1+/CD155+ tumor cells. Single-cell cytokine proteomics showed significant increase in polyfunctionality of UltraCAR-T with intrinsic downregulation of CPI gene(s). In vivo, a single infusion of receptor tyrosine kinase-like orphan receptor 1 (ROR1)-specific UltraCAR-T with intrinsic PD-1 blockade resulted in rapid expansion, an increase in preferred T cell memory (TSCM/TCM) populations, and significantly improved overall survival of ROR1+ PD-L1+ tumor bearing mice. These preclinical data highlight the improved efficacy of incorporating intrinsic CPI blockade in UltraCAR-T cells using non-viral gene delivery and an established rapid, decentralized manufacturing process. Citation Format: Tim Chan, Cheryl Bolinger, Sean Scott, Mengyan Du, Carol Poortman, Byron Koenitzer, Taranjit Athwal, Lindsey Shepard, R. Daniel Slone, Shourik Dutta, Steven Zilko, James M. Dunleavey, Giorgio Zenere, Jacques Plummer, Bernward Klocke, Christian Zinser, Shamim Ahmad, Douglas E. Brough, Rutul R. Shah, Helen Sabzevari. Incorporation of intrinsic checkpoint blockade enhances functionality of multigenic autologous UltraCAR-T® cells manufactured using non-viral gene delivery and rapid manufacturing process [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2821.
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Ramirez-Solis, Edgar. "Succession Planning and its Impact on Business Performance: A bibliometric Method to Identify Future Research in Family Firms". Journal of Global Entrepreneurial Management 1, n.º 1 (2023): 1–12. http://dx.doi.org/10.59462/jgem.1.1.103.
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Our study employs a multifaceted bibliometric analysis to map the intellectual landscape of succession planning in family businesses and its impact on performance. It was based on articles from the Web of Science database from 2017 to 2023. Utilizing VOSviewer software for the analysis, various mapping techniques such as co-authorship networks, geographical dispersion, and keyword co-occurrence were deployed. The findings underscore an increasing scholarly interest in family business succession yet point out a waning emphasis on the planning aspects and their direct implications for business performance. Notably, the study detects a substantial research gap in the Latin American context, suggesting potential for socially and practically high-impact contributions. This study enhances the existing literature by revealing these nuanced trends and gaps and employs a unique methodological approach, using bibliometric analysis to highlight critical interconnections between crucial terms. Thus, the research paves the way for future academic endeavors while offering practitioners actionable insights.
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Lerner, Gabriel B. W., Gary G. Singer, Christopher P. Larsen e Tiffany N. Caza. "Immunoglobulin-Negative Fibrillary Glomerulonephritis Masked in Diabetic Nephropathy: A Case Report and Discussion of a Diagnostic Pitfall". Glomerular Diseases 2, n.º 2 (7 de outubro de 2021): 95–99. http://dx.doi.org/10.1159/000520071.
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<b><i>Introduction:</i></b> Fibrillary glomerulonephritis (FGN) is a rare glomerular disease with poor prognosis, characterized by deposition of randomly arranged fibrillar material measuring 10–30 nm in diameter. This diagnosis is confirmed with DNAJB9 immunohistochemistry as well as ultrastructural examination. Ultrastructurally, the fibrillary material seen in this entity may be confused with diabetic fibrillosis occurring in diabetic nephropathy. <b><i>Case Presentation:</i></b> We present a case of a 63-year-old African American male with remote hepatitis C virus (HCV) infection and type II diabetes mellitus who presented with chronic kidney disease and nephrotic range proteinuria. A kidney biopsy revealed PAS-positive mesangial matrix expansion consistent with diabetic nephropathy and focal randomly oriented fibril deposition on ultrastructural examination. Immunofluorescence for immunoglobulin G and light chains was negative by both routine and paraffin immunofluorescence. Immunohistochemistry for DNAJB9 was diffusely positive, confirming co-existing FGN. <b><i>Discussion/Conclusion:</i></b> Patients with diabetic nephropathy and FGN have similar clinicopathologic presentations with a slowly progressive onset of kidney failure and proteinuria. In diabetic patients with fibrillary deposits under ultrastructural examination, concurrence of these disease entities must be considered. In this patient with remote HCV infection that was successfully treated years before, it is possible that in the absence of an FGN trigger, there was a loss of antigenicity with a loss of immunoglobulin staining. Therefore, we recommend DNAJB9 immunostaining for patients with remote HCV infection to avoid this diagnostic pitfall. Further studies are needed to determine the potential role of HCV infection in the initiation and etiopathogenesis of FGN.
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Korunka, Christian, e Pascale Carayon. "Continuous implementation of information technology: The development of an interview guide and a cross-national comparison of Austrian and American organizations". Human Factors and Ergonomics in Manufacturing 9, n.º 2 (1999): 165–83. http://dx.doi.org/10.1002/(sici)1520-6564(199921)9:2<165::aid-hfm3>3.0.co;2-0.
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Yellen, Benjamin. "Abstract 2760: Evaluation of functional heterogeneity in the potent responses of single CAR-T effector cells". Cancer Research 83, n.º 7_Supplement (4 de abril de 2023): 2760. http://dx.doi.org/10.1158/1538-7445.am2023-2760.
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Abstract Over the last decade, chimeric antigen receptor (CAR)-T cell immunotherapies have produced some miraculous cures in advanced stage, aggressive leukemias and lymphomas in both children and adults. However, many barriers continue to limit the availability and effectiveness of these therapies, including the lack of reliable potency assays for these cell-based “living” medicines. Unlike molecular medicines, which have well established manufacturing processes, cell based medicines are inherently heterogeneous, and each engineered lot of cells will inevitably have a distribution of growth properties, cytolytic activity, gene expression patterns, and secretion profiles, and it is not clear which cell subpopulations are most correlated with positive clinical outcomes.Here we report results of an evaluation of phenotypic heterogeneity in a population of anti-CD19 CAR-T cells co-cultured with target cells in an array of >300,000 microwells. Our approach uses high throughput time lapse imaging to continually monitor the cell-cell interactions between effector and target cells. We maintained cell viability in the microwells for more than 5 days, which gave us sufficient time to observe the full range of antigen-mediated cell killing phenotypes, and also evaluate growth rates of the potent effector cells. We tracked thousands of individual co-cultures through time lapse imaging, and cell behavior was evaluated and sorted by deep learning algorithms. We were able to quickly identify and retrieve clones that exhibited desirable phenotypes for full molecular characterization.Our analysis shows that three fundamental subpopulations of effector cells can be clearly distinguished and quantified. These are 1) effector cells that kill the targets and then die, 2) effector cells that kill the target and then proliferate, and 3) effector cells that do not kill the target. We further dissect these populations by characterizing their secretion and transcriptomic profiles, to identify further subtype classifications. Citation Format: Benjamin Yellen. Evaluation of functional heterogeneity in the potent responses of single CAR-T effector cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2760.
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Yang, Cuiqing, Fuwei Jiang, Yifang Wang, Tingting Liu, Chao Wang, Qingyang Wang, Qin Wang, Gang Ye, Renhong Tang e Zhuoxiao Cao. "Abstract 4087: Co-expression of membrane bound IL-15 enhanced anti-tumor response of CAR-T". Cancer Research 83, n.º 7_Supplement (4 de abril de 2023): 4087. http://dx.doi.org/10.1158/1538-7445.am2023-4087.
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Abstract Introduction: Chimeric antigen receptors (CARs) T cells have been used successfully to treat patients with hematologic malignancies, but showed less effective in solid tumors. We investigated multiple approaches to engineer and enhance CAR-T activity in solid tumors. It has been previously reported that improvement in the quality of CAR-T cells, through CAR design or manufacturing optimization, could enhance the therapeutic potential of CAR-T cells. One parameter influencing the effectiveness of CAR-T cell therapy is the differentiation status of the final product: CAR-T cells that are less-differentiated and less exhausted are more therapeutically potent. It is well known that IL-2 is the main cytokine used to culture cells for adoptive cell therapy, as it plays an important role in the proliferation and functional effect of T cells. However, it has been noted T cells cultured with IL-2 are phenotypically heterogeneous, being predominantly composed of effector memory cells. In comparison with IL2, IL-15 can induce a memory stem-like T cell phenotype, which is less differentiated and with a superior capacity for cell expansion and survival. Several groups reported that compared with cells cultured with IL-2, CAR-T cells expanded with IL-15 preserve a less-differentiated stem cell memory (Tscm) phenotype and exhibited reduced expression of exhaustion markers, higher antiapoptotic properties, increased proliferative capacity upon antigen challenge, and promoted superior anti-tumor responses in vivo. Method: To provide localized IL-15 mediated signaling to T cells, we constructed a version of IL-15 as a membrane-bound molecule (mIL-15) designed to stimulate T cells in cis and in trans, and mIL-15 is tethered to the cell surface and functions locally to enhance the functionality of the CAR-T cell without systemic delivery of IL-15. Result: Expression of mbIL-15 is shown to enhance T cell expansion, preserve a less-differentiated Tscm phenotype and prevent CAR-T cell exhaustion, leading to longer persistence and an enduring anti-tumor response over the conventional CAR-T cells. Conclusion: We demonstrate that CAR-T activity and persistence can be enhanced by simultaneous expression of mIL-15, which preserves the CAR-T cell Tscm phenotype and improves their metabolic fitness, resulting in superior antitumor activity. These preclinical data support the notion that CAR-T cells are designed and optimized to persist in the hostile tumor microenvironment and potentially improve efficacy against solid tumors. Citation Format: Cuiqing Yang, Fuwei Jiang, Yifang Wang, Tingting Liu, Chao Wang, Qingyang Wang, Qin Wang, Gang Ye, Renhong Tang, Zhuoxiao Cao. Co-expression of membrane bound IL-15 enhanced anti-tumor response of CAR-T. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4087.
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Pransky, Joanne. "The Pransky interview: Dr Maja Matarić, Professor, University of Southern California; Pioneer, field of socially assistive robotics; co-founder of Embodied". Industrial Robot: the international journal of robotics research and application 46, n.º 3 (20 de maio de 2019): 332–36. http://dx.doi.org/10.1108/ir-04-2019-0069.
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Purpose The following paper is a “Q&A interview” conducted by Joanne Pransky of Industrial Robot Journal as a method to impart the combined technological, business and personal experience of a prominent, robotic industry PhD and innovator regarding her pioneering efforts and the challenges of bringing a technological invention to market. This paper aims to discuss these issues. Design/methodology/approach The interviewee is Dr Maja Matarić, Chan Soon-Shiong Distinguished Professor in the Computer Science Department, Neuroscience Program, and the Department of Pediatrics at the University of Southern California, founding director of the USC Robotics and Autonomous Systems Center (RASC), co-director of the USC Robotics Research Lab and Vice Dean for Research in the USC Viterbi School of Engineering. In this interview, Matarić shares her personal and business perspectives on socially assistive robotics. Findings Matarić received her PhD in Computer Science and Artificial Intelligence from MIT in 1994, MS in Computer Science from MIT in 1990 and BS in Computer Science from the University of Kansas in 1987. Inspired by the vast potential for affordable human-centered technologies, she went on to found and direct the Interaction Lab, initially at Brandeis University and then at the University of Southern California. Her lab works on developing human–robot non-physical interaction algorithms for supporting desirable behavior change; she has worked with a variety of beneficiary user populations, including children with autism, elderly with Alzheimer’s, stroke survivors and teens at risk for Type 2 diabetes, among others. Originality/value Matarić is a pioneer of the field of socially assistive robotics (SAR) with the goal of improving user health and wellness, communication, learning and autonomy. SAR uses interdisciplinary methods from computer science and engineering as well as cognitive science, social science and human studies evaluation, to endow robots with the ability to assist in mitigating critical societal problems that require sustained personalized support to supplement the efforts of parents, caregivers, clinicians and educators. Matarić is a Fellow of the American Association for the Advancement of Science (AAAS), Fellow of the IEEE and AAAI, recipient of the Presidential Awards for Excellence in Science, Mathematics & Engineering Mentoring (PAESMEM), the Anita Borg Institute Women of Vision Award for Innovation, Okawa Foundation Award, NSF Career Award, the MIT TR35 Innovation Award, the IEEE Robotics and Automation Society Early Career Award and has received many other awards and honors. She was featured in the science documentary movie “Me & Isaac Newton”, in The New Yorker (“Robots that Care” by Jerome Groopman, 2009), Popular Science (“The New Face of Autism Therapy”, 2010), the IEEE Spectrum (“Caregiver Robots”, 2010), and is one of the LA Times Magazine 2010 Visionaries. Matarić is the author of a popular introductory robotics textbook, “The Robotics Primer” (MIT Press 2007), an associate editor of three major journals and has published extensively.
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Varnavskii, V. "The Chinese Phenomenon of Economic Growth". World Economy and International Relations 66, n.º 1 (2022): 5–15. http://dx.doi.org/10.20542/0131-2227-2022-66-1-5-15.
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Modern China should be considered as an unique experiment and great world project of human civilization, effectively a co-product of the Communist Party of China (CPC) and the West. The centuries-old concept of a free-market economy fell on fertile ground of the hardworking Chinese people and in a short historical period since the beginning of the reform has finally bore fruit. Globalization and digitalization have greatly helped the Chinese economy to expand around the world and have become powerful catalysts for Chinese economic development, providing it with new approaches to doing business. The article attempts to analyze this phenomenon and systematize the factors of China’s growth. Key aspects of the Chinese economy transformation are studied, such as GDP (in current and constant prices) and GNI per capita, manufacturing and trade, finance and capital. Special attention is paid to the global leadership role of China or/and the USA: Economy, Manufacturing, and International Trade. An in-depth comparative analysis of the economic growth indicators for China and the USA is based on extensive international statistical data. The author focuses on estimates of key indicators published by international bodies, such as the United Nations, UNCTAD, UNIDO, OECD, WTO and others. Various think tanks, independent agencies and other institutions such as McKinsey Global Institute, Primakov Institute of World Economy and International Relations RAS, Congressional Research Service (CRS), United States–China Economic and Security Review Commission, Committee on Foreign Investment in the United States (CFIUS) have been analyzing Chinese phenomenon of economic growth. Quantitative assessments of China’s economic growth are discussed. As shown, China plays a major role in the world economy and manufacturing. It is now the world’s first country by many economic indicators. In 2007, China became the world’s largest merchandise exporter. In 2009, it took the 1st place in manufacturing value-added output. Measured by purchasing power parity (PPP), in 2017 China stood as the world-largest economy in terms of GDP in current US dollars. Over the past decade, China has provided at least 30 percent of global GDP growth, while the United States was half as much. China is in the world’s top two for receiving and being the source of foreign direct investment (FDI). In 2020, China had 124 Global Fortune 500 companies compared to 121 American. At the same time, the US remains the world leader in many other quantitative indicators, for example in GDP at official exchange rates, innovation, research and development, finance, and services. It also ranks first in the world in terms of quality indicators of economic development. The author gives his vision of the China’s economic growth fundamental factors. Four of them are identified: a) low labor costs, b) well-designed legal environment for attracting foreign capital, c) massive FDI influx, d) imports of capital goods as well as modern Western technologies, including transfer of critical technologies, intellectual property and know-how (mainly through acquisition of Western firms). The general conclusion is that the reforms completely transformed the lives of Chinese people. China of the 1970s 80s and today’s China are two different economic, industrial, scientific, technical, socio-humanitarian entities.
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Woolford, Andrew, Wanda June e Sereyvothny Um. "“We Planted Rice and Killed People:” Symbiogenetic Destruction in the Cambodian Genocide". Genocide Studies and Prevention 15, n.º 1 (maio de 2021): 44–67. http://dx.doi.org/10.5038/1911-9933.15.1.1805.
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In recent years, genocide scholars have given greater attention to the dangers posed by climate change for increasing the prevalence or intensity of genocide. Challenges related to forced migration, resource scarcity, famine, and other threats of the Anthropocene are identified as sources of present and future risk, especially for those committed to genocide prevention. We approach the connection between the natural and social aspects of genocide from a different angle. Our research emanates out of a North American Indigenous studies and new materialist rather than Euro-genocide studies framework, meaning we see the natural and the social (or cultural) as inseparable, deeply imbricated, phenomena. We argue that those entities designated natural are often engaged in co-constitutive relations with the social and cultural groups that are the focus of genocide studies. Simply put, groups become what they are through interaction—or symbiogenesis—with their natural world(s). Symbiogenetic destruction, then, is the destruction of this symbiogenesis. We use this term to draw attention to how relations with more-than-human entities are integral components of the ongoing formation of group life, and how they are put at risk by genocide. In particular, we examine testimony that centers on the relationship between Khmer people and rice, including rice cultivation and consumption, as it was impacted by the Khmer Rouge. In so doing, we highlight the cultural consequences of social/natural death in the Cambodian genocide.
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Pedro, Kyle D., Rachel Burga, Alonso Villasmil Ocando, Meghan Langley, Gauri Kulkarni, Zheng Ao, Benjamin Primack et al. "Abstract LB096: IL15-engineered tumor infiltrating lymphocytes (cytoTIL15TM) exhibit activity against autologous tumor cells from multiple solid tumor indications without IL2". Cancer Research 83, n.º 8_Supplement (14 de abril de 2023): LB096. http://dx.doi.org/10.1158/1538-7445.am2023-lb096.
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Abstract Tumor infiltrating lymphocyte (TIL) therapy has shown promising results in the treatment of metastatic melanoma. However, TIL therapy has conventionally required co-administration of IL2, which is associated with toxicity in patients. We previously showed that melanoma TILs engineered to express membrane-bound IL15 (mbIL15) under the control of the ligand acetazolamide (ACZ) can achieve IL2-independent expansion during manufacturing, antigen-independent persistence in vitro and anti-tumor efficacy in vivo. In the current study, we extend the cytoTIL15 cell therapy product concept to indications beyond melanoma including non-small cell lung cancers (NSCLC), triple-negative breast cancers (TNBC) and head and neck squamous cell carcinomas (HNSCC), tumor types which represent significant unmet medical needs, particularly in the post-checkpoint inhibitor refractory setting. TILs from primary NSCLC, HNSCC and TNBC were engineered to express mbIL15 in the presence of ACZ and expanded in the absence of IL2 using our proprietary rapid expansion protocol (REP). CytoTIL15 cells were predominantly CD8 positive, enriched for mbIL15 expression and maintained T cell receptor variable beta chain (TCRVβ) diversity throughout expansion. In vitro antigen- and cytokine-independent survival and polyfunctionality of cytoTIL15 cells was measured from cultures that included ACZ. To assess anti-tumor activity, cytoTIL15 cells were co-cultured with autologous patient-derived cell lines (PDc) or tumor digests from patient-derived xenografts (PDx), and cytotoxicity and IFNγ release into supernatant was measured. In vitro, cytoTIL15 cells + ACZ exhibited similar or increased polyfunctionality compared to unengineered TIL + IL2. Unlike unengineered TILs, cytoTIL15 cells + ACZ persisted in an antigen-free setting without IL2, were cytotoxic to autologous PDc and released IFNγ in response to autologous PDx tumor digest. Taken together, these data show that IL2-independent, fully functional cytoTIL15 cells can successfully be generated from tumors such as NSCLC, HNSCC & TNBC, which afflict large numbers of patients. Citation Format: Kyle D. Pedro, Rachel Burga, Alonso Villasmil Ocando, Meghan Langley, Gauri Kulkarni, Zheng Ao, Benjamin Primack, Theresa Ross, Violet Young, Jeremy Tchaicha, Michelle Ols, Jan Ter Meulen. IL15-engineered tumor infiltrating lymphocytes (cytoTIL15TM) exhibit activity against autologous tumor cells from multiple solid tumor indications without IL2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB096.
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Brown, Alan S. "Staying Alive". Mechanical Engineering 128, n.º 01 (1 de janeiro de 2006): 22–26. http://dx.doi.org/10.1115/1.2006-jan-1.
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This article provides details of small US companies that are competing with Chinese counterparts and earning profits as well. Elnik Systems keeps costs under control by importing expensive molybdenum and tungsten furnace metals from China. It also outsources predrilled molybdenum furnace tray preforms, but must bend them into shape in the United States to achieve the quality it requires. Irwin Industrial Tool Co. sets aggressive cost goals each year, relying on employee teams and ongoing investment to drive down unit costs. It has reduced headcount, sought better deals from suppliers, and even outsourced its warehouse. Reducing costs cuts the premium Irwin needs to charge to profit from making Vise-Grips in DeWitt. As long as ‘Made in America’ means a better product, it can continue to do that. In many ways, the engineering plastic injection molding business of Donnelly Custom Manufacturing Co. in Alexandria, Minn. resembles the short-run, fast-turnaround model of New York's Liberty Brass Turning. Despite his success, Donnelly worries about America's manufacturing future. Donnelly exited the business before it all went to China. Now he questions whether other start-ups would go to a local source or deal directly with China.
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Jeong, Joseph H., Young-Kyun Chang, You-Yeon Kang, Jeong-Yun Lee, Sae-Rom Lee, Yun-Kyung Lee, Young-Ho Kim e Byoung S. Kwon. "Abstract LB090: IL-18 secreting chimeric antigen receptor T cells targeting glypican-3show superior persistence and antitumor immunity against hepatocellular carcinoma". Cancer Research 83, n.º 8_Supplement (14 de abril de 2023): LB090. http://dx.doi.org/10.1158/1538-7445.am2023-lb090.
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Abstract Over the last decade, immunotherapy has revolutionized the way we treat cancer primarily by boosting the body’s own immune system to help fight cancer. In particular, an engineered T cell therapy, namely chimeric antigen receptor (CAR) T cell therapy, is a more aggressive way to modify T cells to recognize cancer cells and destroy them. Although these CAR-T therapies have shown remarkable clinical responses in patients with hematological malignancies, their efficacy in solid tumor treatment has been disappointing due to many challenges: lack of tumor-specific antigen targets, loss of the CAR T-cell persistence, the inability of CAR-T cells to effectively infiltrate into solid tumors, toxicities of cytokine release syndrome and neurologic toxicity, and the immunosuppressive tumor microenvironment (TME). In this regard, we report here that we have successfully developed a CAR-T cell therapy, referred to as EU307, to treat one type of solid tumor, hepatocellular carcinoma (HCC). EU307 is a fourth-generation CAR-T therapy that targets the HCC-specific tumor antigen of glypican-3 (GPC3), and also secretes IL-18 which results in autocrine co-stimulation of CAR-T cells and reprogramming of the TME into a tumor-killing environment. Through a sophistically optimized manufacturing process in our good manufacturing practices (GMP) facility, we are able to manufacture CAR-T cells with stem cell memory (TSCM) and central memory (TCM) phenotypes. Functionally, EU307, when infused with as little as 0.1 × 106 total cells per animal, showed superior in vivo persistence and antitumor immunity in an HCC tumor-bearing mouse model. Furthermore, a single dose toxicity study in the same disease mouse model determined the no observed adverse effect level (NOAEL) as 5.0 × 105 total cells per male and 1.0 × 106 total cells per female. Taken together, our studies demonstrate that we have a developed a novel fourth-generation CAR-T therapy to treat HCC, a solid tumor that expresses a high-level of tumor-specific GPC3, by overcoming previously limiting factors in the development of CAR-T therapies against solid tumors. Citation Format: Joseph H. Jeong, Young-Kyun Chang, You-Yeon Kang, Jeong-Yun Lee, Sae-Rom Lee, Yun-Kyung Lee, Young-Ho Kim, Byoung S. Kwon. IL-18 secreting chimeric antigen receptor T cells targeting glypican-3show superior persistence and antitumor immunity against hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB090.
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Certo, Michael, Christopher Baldeviano, Sharlene Adams, Martin Asimis, Alexander Astrakhan, Andy Chavkin, Maria L. Cabral et al. "Abstract 581: bbT369, a dual-targeted and CBLB gene-edited autologous CART product, demonstrates anti-lymphoma activity in preclinical mouse models". Cancer Research 82, n.º 12_Supplement (15 de junho de 2022): 581. http://dx.doi.org/10.1158/1538-7445.am2022-581.
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Abstract Anti-CD19 CAR T cell therapies have improved outcomes for non-Hodgkin lymphoma (NHL) patients. However, only 30-40% of patients treated with commercially available CART cell therapies obtain long term remission, highlighting the need for more efficacious and durable therapies. Emerging clinical data suggest several failure modes for CD19 CAR T cell therapies: including loss or downregulation of CD19 antigen, loss of co-stimulation pathways on tumor cells, exhaustion of CAR-T cells, and immunosuppressive microenvironments. To overcome these hurdles, we devised the next-generation autologous CAR-T cell therapy bbT369. bbT369 is dual targeted (CD79a/CD20) CAR T cell therapy that uses an OR gate design to limit antigen escape, has split 41BB and CD28 co-stimulatory domain architecture to augment T cell activation, and contains a knock-out of the CBLB gene to enhance potency and reduce T cell exhaustion. Here we report the first results with bbT369, demonstrating anti-lymphoma activity in in vitro assays and in vivo using xenograft mouse models. We demonstrate that CD79a and CD20 expression is B cell lineage restricted in normal human tissue and confirm that these proteins are co-expressed in diffuse large B cell samples. To target these antigens, we show a split dual-targeting CAR configuration is optimal for bbT369-directed tumor cell killing. Using an engineered megaTAL, we demonstrate high on-target activity of greater than 75% insertions and deletions (Indels) at the CBLB target site using clinical-scale manufacturing processes and low off-target activity (all off-targets less than 0.2%). In in vitro tumor co-culture assays, we show that inclusion of the CBLB gene edit in bbT369 increases Interleukin (IL)-2 production relative to an unedited anti-CD79a/CD20 CAR T cell control. Using various xenograft mouse models, we showed that bbT369 has similar or improved efficacy compared to anti-CD19 CAR drug product, including in low tumor-antigen models. In the Toledo subcutaneous xenograft model, bbT369 showed a 3-fold increase in T cell expansion compared with an unedited anti-CD79a/CD20 dual-targeting CAR T cell control. Furthermore, while a fraction of mice (3/5) receiving the unedited anti-CD79a/CD20 dual-targeting CAR T cells experienced late relapses (between 60-80 days following initial tumor clearance), all mice (n=5) receiving bbT369 were fully protected from late relapses (up to day 104 of follow-up). Collectively, the data support a first-in-human trial for bbT369 to evaluate initial safety and efficacy in NHL patients. Citation Format: Michael Certo, Christopher Baldeviano, Sharlene Adams, Martin Asimis, Alexander Astrakhan, Andy Chavkin, Maria L. Cabral, Jimmy Chu, Marie Debrue, Devina Desai, John Evans, Pinky Htun, Amanda Iniguez, Jordan Jarjour, Carl Johnson, Harini Kantamneni, Sema Kurtulus, Michael Magee, Unja Martin, Seamus McKenney, Sara Miller, Prashant Nambiar, Vinh Khang Nguyen, Mauris Nnamani, Jen Obrigewitch, Lisa Pechilis, Molly Perkins, Christopher Petersen, Jason Pinger, Cindy Rogers, Nick Rouillard, Kendal Sanson, Emily Thompson, Collin Walter, Roslyn Yi, Sarah Voytek, Philip Gregory. bbT369, a dual-targeted and CBLB gene-edited autologous CART product, demonstrates anti-lymphoma activity in preclinical mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 581.
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Haq, Naeem Ul, Hayat Mohammad Khan, Musawer Khan, Mohammad Ishaq, Muhammad Usman e Gohar Ali. "Clinical Features and Surgical Management of Intracranial Meningioma’s in the Elderly". Scholars Journal of Applied Medical Sciences 10, n.º 7 (23 de julho de 2022): 1105–12. http://dx.doi.org/10.36347/sjams.2022.v10i07.011.
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Objective: Given the threat related with surgical intervention of intracranial meningiomas in the older population because of maturing physiology and numerous co morbidities, an endeavor was made to distinguish mediators impacting results and to characterize a category of individuals who ought not be surgically treated because of deprived prognosis. Study Setting: The study was conducted in neurosurgery unit mardan medical complex / bacha khan medical college Name of Hospital, Pakistan. Methods: The investigation of 58 individuals over the age of 70 years was conducted to determine short- and long-term results. Additionally, we derived scores for our patients using the previously reported CRGS, SKALE, and GSS grading systems. Result: As per the SKALE reviewing framework, neurological grimness was exclusively associated with a crucial site (P=0.02). Six people (10.3 percent) capitulated to their wounds. The Karnofsky score (KPS 60 versus KPS 70; P=0.0162), the American Society scale status (ASA 1 or 2 versus ASA 3; P=0.0022), and the evaluation of meningioma’s were totally connected with mortality (P=0.012). The WHO grade (P=0.00048) and Simpson evaluation of resection (P=0.0437) were related with tumor repetition in six cases. Except for patients who died because of medical procedure or reoccurrence (15.5%), majority of subjects improved (50%) or remain unaltered (25.9%) in contrast with their karnofsky score before surgery. Conclusion: Neurological impairment following surgery was only observed in patients with a significant tumor placement (skull base, eloquent area, large vessels indulgence by the tumor). Because of the greatly increased threat of fatality, surgery should be carefully considered in individuals with a low functional state (KPS 60) or a bad bodily state (ASA 3 status). During routine visits, the majority of patients’ neurological health enhanced or remains constant in comparison to their condition before operation.
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Abdou, Yara, E. Claire Dees, Joanne Mortimer, Naoto Ueno, Melissa Johnson, Richard Maziarz, Jennifer Specht et al. "Abstract CT241: A phase 1, first-in-human (FIH) study of autologous anti-HER2 chimeric antigen receptor macrophage (CAR-M) in participants (pt) with HER2 overexpressing solid tumors". Cancer Research 83, n.º 8_Supplement (14 de abril de 2023): CT241. http://dx.doi.org/10.1158/1538-7445.am2023-ct241.
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Abstract Background: Macrophages are abundant in the solid tumor microenvironment (sTME) and can exhibit both pro- and anti-tumor functions. Macrophages can be redirected by CAR expression to phagocytose cancer cells in an antigen-specific manner. CAR-M can reprogram the sTME and present neoantigens to T cells, leading to epitope spreading and anti-tumor immunity. CT-0508 is comprised of autologous monocyte-derived proinflammatory macrophages expressing an anti-HER2 CAR. Pre-clinical studies showed that CT-0508 induced targeted cancer cell phagocytosis while sparing normal cells, decreased tumor burden, prolonged survival, and was safe and effective. Notably, anti-HER2 CAR-M treatment led to activation of the sTME, with infiltration of CD8+ and CD4+ T cells, NK cells, dendritic cells, and increased activated CD8+ tumor infiltrating lymphocytes. In a pre-clinical model of advanced solid tumor resistant to PD1 blockade, mice treated with anti-HER2 CAR-M combined with a PD1 blocking antibody demonstrated improved tumor control, overall survival, and TME activation compared to either treatment alone, indicating synergy and capacity for CAR-M to sensitize solid tumors to checkpoint blockade. Methods: This Phase 1, FIH study is evaluating safety, tolerability, cell manufacturing feasibility, trafficking, TME activation, and preliminary evidence of efficacy of investigational product CT-0508 in 18 pt with locally advanced (unresectable)/metastatic solid tumors overexpressing HER2. Pt previously treated with anti-HER2 therapies are eligible. Filgrastim mobilized autologous CD14+ monocytes are collected by apheresis, followed by manufacturing and cryopreservation. Group 1 pt (n = 9; enrollment complete) received fractionated doses over Days 1, 3, and 5. Group 2 pt (n = 9) receive CT-0508 as a single infusion on D1. Additional cohorts include: CT-0508 co-administered with pembrolizumab and CT-0508 monotherapy administered intraperitoneally in pt with peritoneal predominant disease. Correlative assessments include pre- and post-treatment biopsies and blood samples for safety (immunogenicity), trafficking (qPCR, RNA in situ hybridization), CT-0508 persistence in blood and tumor, target antigen engagement, TME modulation (single cell RNA sequencing), immune response (TCR sequencing) and others. Citation Format: Yara Abdou, E. Claire Dees, Joanne Mortimer, Naoto Ueno, Melissa Johnson, Richard Maziarz, Jennifer Specht, Yuan Yuan, Paula Puhlman, Mathew Angelos, Saar Gill, Amy Ronczka, Thomas Condamine, Daniel J. Cushing, Michael Klichinsky, Debora Barton, Ramona F. Swaby, Kim Reiss Binder. A phase 1, first-in-human (FIH) study of autologous anti-HER2 chimeric antigen receptor macrophage (CAR-M) in participants (pt) with HER2 overexpressing solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT241.
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Roy, Jaydeep, Nga Tin Lin, Kronos Chow, Chih Ya Yang, James C. L. Lin, John M. Luk e Kwong F. Wong. "Abstract 1326: Pre-clinical development of ARB011: A CDH17 targeting allogeneic nonviral RNA-based “Flash” CAR-NK therapy for gastrointestinal cancer". Cancer Research 84, n.º 6_Supplement (22 de março de 2024): 1326. http://dx.doi.org/10.1158/1538-7445.am2024-1326.
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Abstract Background: Treatment for advanced gastrointestinal (GI) cancers has remained challenging, therefore, novel immunotherapies using chimeric antigen receptor (CAR)-T cells are being developed as a new hope for the patients. However, despite the clinical successes in hematologic malignancies, the overall safety and efficacy against solid tumors of CAR-T cells have yet to be established, and the manufacturing of autologous CAR-T cells requires lengthy cell expansion and viral transduction processes. In view of these technical challenges, we have developed ARB011, an RNA-based allogeneic CAR-NK therapy targeting GI cancers expressing cadherin-17 (CDH17), a promising therapeutic target with its overexpression associated with poor prognosis in patients with GI cancers. The use of allogeneic NK cells would mitigate the risk of graft-versus-host disease. Moreover, engineering NK cells with nonviral CAR-encoding mRNA would provide a rapid large-scale manufacturing platform with minimal risk of abnormal genetic alteration mediated by viral integration. Methods: To generate the ARB011 CAR-NK cells, ex vivo expanded human peripheral blood NK (Magicell-NK, Medigen, Taiwan) cells were electroporated with mRNA encoding a humanized anti-CDH17 scFv fused with transactivation domains. Flow cytometry, in vitro cytotoxicity assay, and cytokine release assay were performed to evaluate the expression and functionality of ARB011. To examine the developability of ARB011 as an off-the-shelf cell product, cryopreservation and large-scale electroporation were also studied. Results: Flow cytometry analysis revealed efficient electroporation with a high level of CDH17 CAR expression (>80%) and optimal CAR-NK cell viability (60%-80%). Following electroporation, cytotoxicity of ARB011 was tested against gastric (AGS and NCI-N87), colorectal (DLD-1 and T84), and liver (MHCC-97H) cancer cells by co-culturing at 1:1 and 2:1 effector/target ratio for 12-24h. ARB011 showed significant cytotoxicity against CDH17+ but not CDH17- cancer cells. The CDH17-sepcific cytotoxicity was accompanied with elevated levels of CD107a or LAMP-1 expression on CAR-NK cells and IFN-γ and TNF-α releases. Interestingly, cryopreserved ARB011 maintained optimal cell viability, CAR expression, and potent CDH17 target-specific cytolytic activity. Lastly, large-scale electroporation showed the establishment of up-scaling process of ARB011 production for clinical application. Conclusions: Overall, the findings suggest that ARB011 could be a novel off-the-shelf, CAR-NK therapy that warrants further studies in animal models and in clinical trials. Citation Format: Jaydeep Roy, Nga Tin Lin, Kronos Chow, Chih Ya Yang, James C.L. Lin, John M. Luk, Kwong F. Wong. Pre-clinical development of ARB011: A CDH17 targeting allogeneic nonviral RNA-based “Flash” CAR-NK therapy for gastrointestinal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1326.
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Sitrin, Jonathan, Lisa Marshall, Hai Tran, Kenneth Ng, Kimberly Hoi, Josef Gramespacher, Zhong Huang et al. "Abstract 1866: Discovery of mutation-independent EGFR degrading bispecific antibodies that suppress tumor growth in preclinical tumor models". Cancer Research 84, n.º 6_Supplement (22 de março de 2024): 1866. http://dx.doi.org/10.1158/1538-7445.am2024-1866.
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Abstract Extracellular targeted protein degradation (eTPD) has emerged as a promising new drug modality focused on targeted elimination of extracellular and transmembrane proteins. In contrast to intracellular protein degraders, such as proteolysis targeting chimeras (PROTACs) and molecular glues which require ubiquitin-proteosome cellular degradation pathways, extracellular protein degraders can additionally harness endosomal-lysosomal protein degradation. Two recently published examples of extracellular protein degraders include AbTACs (antibody-based PROTAC) which co-engage a protein of interest (POI) and transmembrane E3 ligases, and KineTACs (cytokine receptor-targeting chimeras) which utilize endogenous cytokine receptors to degrade extracellular POIs. These bispecific antibody degrader platforms not only have advantageous pharmacological and drug-like manufacturing properties, but can also be engineered for tissue-specificity and to address multiple complementary targets, with the goal of increased efficacy and decreased toxicity. To that end, we have greatly expanded the extracellular degrader repertoire beyond AbTACs and KineTACs, with a novel bispecific antibody degrader platform called TrainTACs (tissue receptor antigen internalization targeting chimeras). To demonstrate the potential of this novel extracellular degrading platform, we developed degraders for the canonical receptor tyrosine kinase epidermal growth factor receptor (EGFR). EGFR is an oncogenic driver, that has been clinically validated in lung, colorectal and head and neck cancers, but patient benefit has been limited by treatment-related acquired resistance mutations and on-target/off-tumor dose-limiting toxicities. The potential of our TrainTACs, AbTACs and KineTACs to overcome the limitations of current therapeutic modalities was assessed. Gene expression profiles from tumor and normal tissues were evaluated to identify potential degraders co-expressed with EGFR in tumors. More than 70 unique bispecific antibody constructs spanning 20 receptors were generated and screened in tumor cell-based assays to evaluate EGFR antagonism, internalization, and degradation. TrainTACs, AbTACs and KineTACs degraded EGFR in multiple tumor cell lines covering a range of EGFR mutations. Degradation of EGFR led to deep inhibition of EGFR signaling, robust inhibitory effects on tumor spheroids, and in xenograft mouse tumor models. In conclusion, eTPD represents a promising new drug modality, and TrainTACs, AbTACs and KineTACs have expanded the toolbox of extracellular targeted protein degraders that can be utilized in a target-, tissue- and disease-specific manner. Citation Format: Jonathan Sitrin, Lisa Marshall, Hai Tran, Kenneth Ng, Kimberly Hoi, Josef Gramespacher, Zhong Huang, Andy Goodrich, Filomena Housley, May Dayao, Man-Tzu Wang, Katarina Pance, Aleysha Chen, Kevin Carlin, Lichao Zhang, James Lee, Rami Hannoush, Ken Flanagan, Maia Vinogradova, Isaac Rondon, Shyra Gardai. Discovery of mutation-independent EGFR degrading bispecific antibodies that suppress tumor growth in preclinical tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1866.
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Mazhara, G. A. "Modeling of the Optimal Investment Portfolio Focused on Risk Minimization". Modern Economics 38, n.º 1 (20 de abril de 2023): 69–75. http://dx.doi.org/10.31521/modecon.v38(2023)-11.
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Abstract. Introduction. Portfolio optimization modelling is a study aimed at determining the best way to allocate an investor's funds between securities of different companies. The study uses a number of methods and approaches, such as: multicriteria optimization methods - optimization of criteria for minimum and maximum, modeling of the optimal stock portfolio with minimal risk, to determine the best way to allocate funds that will help investors achieve maximum return while minimizing risk. Purpose. There are a lot of publicly traded companies in the modern American stock market. Having chosen the companies that may grow in the future, the problem of allocating your funds among them remains relevant. Building an optimal portfolio of securities using various economic and mathematical methods solves the problem of allocating financial resources, focusing on the desired future profit and the level of risk exposure. Results. The model for this study was built using one of the methods of multi-criteria optimization - criteria convolution, taking into account portfolio diversification and the specified constraints. The optimization is based on the "Modern Portfolio Theory" of the prominent scientist Harry Markowitz. Conclusions. As a result, we built an optimal and diversified portfolio of shares, in which each company on the list represents at least 1%. All constraints have been met and the main conditions have been fulfilled - the portfolio minimizes risk and maximizes profit. With a minimum risk of 5.39%, we expect a return of 1.75%. Such results can be obtained if we use a convolution of the criteria where the preference is given to minimizing risk - 0.7. The largest contributors to the portfolio were the following companies: T-Mobile Us Inc., McKesson Corporation, The Kroger Co., Microsoft Corporation, and Apple Inc. These companies account for a significant portion of the portfolio - 65%. Given the focus on portfolio diversification and the ratio of risk to potential return, we can say that the portfolio is efficient and can be used in practice.
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Rosoff, Nancy. "Climate in Crisis: Art and Activism at the Brooklyn Museum". Genocide Studies and Prevention 16, n.º 1 (julho de 2022): 101–19. http://dx.doi.org/10.5038/1911-9933.16.1.1867.
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This paper explores the Brooklyn Museum’s activism-centered museum practice as exemplified by the exhibition Climate in Crisis: Environmental Change in the Indigenous Americas. The exhibition presents the collections of Indigenous art from North, Central, and South America through the lens of climate change and its impact on the survival of Indigenous people. The main thesis is that the current climate emergency is part of a longer history of environmental colonialism that began five hundred years ago. For millennia, Indigenous communities throughout the Americas have maintained profound and expansive relationships with the natural world. However, beginning in the 1500s, Europe’s conquest and colonization of the Americas forced ways of using natural resources that clashed with traditional Indigenous modes of relating to the world. This fundamental difference in worldview—between one that sees human beings, animals, plants, and the land as interrelated and co-equal, and another that privileges human needs above everything else—has resulted in ever-escalating threats to Indigenous homelands, ways of life, and survival, as well as the unprecedented level of climate change affecting the planet today.
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Pransky, Joanne. "The Pransky interview: Dr Howard Chizeck, founder, Olis Robotics; Professor, Electrical and Computer Engineering, University of Washington". Industrial Robot: the international journal of robotics research and application 46, n.º 4 (17 de junho de 2019): 467–70. http://dx.doi.org/10.1108/ir-05-2019-0102.
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Purpose The following paper is a “Q&A interview” conducted by Joanne Pransky of Industrial Robot Journal as a method to impart the combined technological, business and personal experience of a prominent, robotic industry PhD and innovator regarding his pioneering efforts and his personal journey of bringing a technological invention to market. This paper aims to discuss these issues. Design/methodology/approach The interviewee is Dr Howard Chizeck, Professor of Electrical and Computer Engineering and Adjunct Professor of Bioengineering at the University of Washington (UW). Professor Chizeck is a research testbed leader for the Center for Neurotechnology (a National Science Foundation Engineering Research Center) and also co-director of the UW BioRobotics Laboratory. In this interview, Chizeck shares the details on his latest startup, Olis Robotics. Findings Howard Jay Chizeck received his BS and MS degrees from Case Western Reserve University and the ScD degree in Electrical Engineering and Computer Science from the Massachusetts Institute of Technology. He served as Chair of the Department of Systems, Control and Industrial Engineering at Case Western Reserve University and was also the Chair of the Electrical and Computer Engineering Department at the University of Washington. His telerobotic research includes haptic navigation and control for telerobotic devices, including robotic surgery and underwater systems. His neural engineering work involves the design and security of brain-machine interfaces and the development of devices to control symptoms of essential tremor and Parkinson’s disease. Originality/value Professor Chizeck was elected as a Fellow of the IEEE in 1999 “for contributions to the use of control system theory in biomedical engineering” and he was elected to the American Institute for Medical and Biological Engineering (AIMBE) College of Fellows in 2011 for “contributions to the use of control system theory in functional electrical stimulation assisted walking.” From 2008 to 2012, he was a member of the Science Technology Advisory Panel of the Johns Hopkins Applied Physics Laboratory. Professor Chizeck currently serves on the Visiting Committee of the Case School of Engineering (Case Western Reserve University). He is a founder and advisor of Controlsoft Inc (Ohio) and also is a founder and Chair of the Board of Directors of Olis Robotics, Inc., which was established in 2013 (under the name of BluHaptics) to commercialize haptic rendering, haptic navigation and other UW telerobotic technologies. He holds approximately 20 patents, and he has published more than 250 scholarly papers.
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Tyllis, Timona, Caitlin Abbott, Dylan McPeake, Jade Foeng, Veronika Bandara, Batjargal Gundsambuu, Silvana Napoli et al. "Abstract 3199: Development of a flow cytometry-based assay for measuring specific CAR expression on LGR5-targeting CAR-T cells". Cancer Research 83, n.º 7_Supplement (4 de abril de 2023): 3199. http://dx.doi.org/10.1158/1538-7445.am2023-3199.
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Abstract The measurement of chimeric antigen receptor (CAR) expression is critical for the development, qualification and quantitation of CAR-T cells for clinical applications. There is a comprehensive range of tools commercially available for specifically measuring expression of the CAR on CD19-targeting CAR-T cells. However, with the rapidly expanding repertoire of CAR-T cells in development targeting a diverse range of tumour antigens, there is a paucity of readily implementable assays that specifically measure CAR expression, which is essential for translation into the clinic. We have developed several CARs targeting the cancer stem cell marker LGR5, one of which (CNA3103) is the lead candidate in an upcoming clinical trial in advanced metastatic colorectal cancer. Previously, the level of CNA3103 expression in this system has been determined indirectly by measuring expression of tEGFR on the CAR-T cell surface, taking advantage of co-expression of the CAR and tEGFR upon transduction with our lentiviral construct. tEGFR expression was found over many CAR-T cell manufacturing batches to report transduction efficiency reproducibly with high sensitivity. However, to specifically quantify expression of the CNA3103, an assay utilising an Fc-tagged recombinant human LGR5 protein, in combination with an anti-human IgG1 Fc-specific secondary antibody was developed. A number of optimisation steps including titration of multiple batches of rhLGR5-Fc, different anti-human IgG1 Fc-specific antibodies and a range of incubation parameters were tested. This resulted in development of an assay that yielded very similar reproducibility and sensitivity to that previously observed with the indirect tEGFR surrogate assay. Overall, the findings highlight the utility of using CAR-targeting recombinant proteins for evaluating CAR expression on CAR-T cells, providing a general flow cytometry-based staining strategy that may be adapted for assessing a diverse repertoire of CARs. Citation Format: Timona Tyllis, Caitlin Abbott, Dylan McPeake, Jade Foeng, Veronika Bandara, Batjargal Gundsambuu, Silvana Napoli, Stuart Mills, Emma Thompson, Lih Tan, Allison Cowin, Claudine Bonder, Timothy Sadlon, Simon Barry, Shaun McColl. Development of a flow cytometry-based assay for measuring specific CAR expression on LGR5-targeting CAR-T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3199.
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Jung, Miyoung, Seung Min Kim, Eunsol Lee, Hyunseung Sun, Jaeyoung Yoo, Hwi Wan Choi, Subin An, Sunglim Cho e Bokyung Min. "Abstract 1324: Superior anti-tumor activity of GL205, an allogeneic anti-CD5 CAR-NK for treating T-cell malignancies". Cancer Research 84, n.º 6_Supplement (22 de março de 2024): 1324. http://dx.doi.org/10.1158/1538-7445.am2024-1324.
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Abstract T cell malignancies are rare and intractable diseases with fewer treatment options and higher unmet needs compared to B-cell lymphomas. Chemotherapy such as CHOP has been used as the standard therapy for treatment of T cell malignancies, but clinical outcome is not a promising and alternative treatments are needed. Currently, Brentuximab Vedotin, an antibody-drug conjugate that targets CD30 is widely used for Hodgkin lymphoma, ALCL and CTCL. However, the application is limited to specific subtypes because CD30 expression is restricted to some subsets of T-cell lymphoma. CD5 is an attractive target for cancer immunotherapy because it is commonly expressed in most of T cell malignancies. Although CD5 CAR-T cell products have demonstrated the anti-cancer efficacy, there are several disadvantages including 1) challenges due to difficulties in manufacturing process caused by fratricide, 2) product contamination by CAR-introduced patient’s malignant T cells, 3) severe side effects such as CRS and neurotoxicity. Therefore, CD5 CAR-NK as allogeneic anti-tumor therapy can be an alternative for treatment of T cell malignancies. GL205, cord blood-derived CD5 CAR-NK, is genetically modified to express CD5-directed CAR and simultaneously produce IL-15 which supports the NK survival and proliferation. GL205 is ex-vivo expanded, cryopreserved cell therapy product comprising of pure NK cells (> 99%) with high CD5 CAR expression (> 90%). GL205 showed significantly higher in vitro direct-killing efficacy against CD5+ tumor cells compared to donor matched CBNK. IFN-γ and IL-15 release from GL205 was significantly increased after co-incubation with CD5+ tumor cells. In xenograft mouse model, GL205 administration exhibited a greater survival rate and low tumor burden compared to vehicle group. In addition, GL205 was detected in blood for 3 months, demonstrating in vivo long-term persistence. In conclusion, GL205 could be a valuable and off-the-shelf allogeneic therapeutic option for treating T cell malignancies. Citation Format: Miyoung Jung, Seung Min Kim, Eunsol Lee, Hyunseung Sun, Jaeyoung Yoo, Hwi Wan Choi, Subin An, Sunglim Cho, Bokyung Min. Superior anti-tumor activity of GL205, an allogeneic anti-CD5 CAR-NK for treating T-cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1324.
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Lopez-Lago, Miguel A., Vikas Bhardwaj, Xiaoyi Zheng, Sagarika pachhal, Renee Cortez, Charles Wiseman e William Williams. "Abstract 685: Engineering semi-allogeneic whole cancer vaccines with enhanced immunogenicity for the treatment of advanced solid tumors". Cancer Research 83, n.º 7_Supplement (4 de abril de 2023): 685. http://dx.doi.org/10.1158/1538-7445.am2023-685.
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Abstract Background: Therapeutic cancer vaccines are designed to program a patient’s own immune system to recognize and eliminate tumor cells. We sought to harness gene-modified tumor cells as a vaccine platform and developed cancer vaccines composed of breast cancer cells expressing GM-CSF (SV-BR-1-GM). We have recently reported favorable clinical outcomes in patient populations that match SV-BR-1-GM at one or more HLA alleles. Mechanistically, SV-BR-1-GM cells can directly activate CD4+ T-cells in an antigen-specific HLA-restricted manner, as demonstrated by an in vitro antigen presentation assay (1). All these observations led us to hypothesize that semi-allogeneic cell-based cancer vaccines (partially matching host HLA genotype) would mount an enhanced immune response by forcing the host immune response to recognize tumor-associated antigens in the context of allogeneic HLA-I or II molecules or in proximity of strong non-self-antigens. Therefore, steps were taken to generate semi-allogeneic cancer cell lines expressing an extended repertoire of stimulatory molecules to induce optimal immune activation (Bria-OTS). Methods: SV-BR-1 (Breast cancer), PC-3 (prostate cancer), SK-MEL-24 (Melanoma), and NCI-H2228 (Lung cancer) were selected for vaccine development. To generate semi-allogeneic cell lines matching >99% of the population at least at 1 HLA allele, four cell lines (for each parental tumor cell line) were developed, each carrying two (2) HLA-A and two (2) HLA-DRB3/4/5 alleles, for a total of eight HLA-A and seven HLA-DRB3/4/5 alleles. We transduced selected co-stimulatory molecules and immune-modulatory cytokines. Next, the unique combinations of HLA-A and HLA-DRB3/4/5 alleles were transduced into the cells using lentiviral based vectors. Finally, functionality of the engineered cells was validated by using molecular and cellular based assays. Preliminary data: Four cell lines (for each tumor type) that secreted GM-CSF, IFNα, IL12, IL7 and expressed CD80, CD86, 4-1BBL, and different combinations of both Class I and Class II HLA alleles were selected. Using cell-based assays - including mixed lymphocyte reaction assays -, we demonstrated that the generated cells stimulate naïve T-cells. Evaluation of the cells ability to present antigens in an HLA-restricted antigen-specific manner is also planned. Discussion and conclusions: Different types of cancer vaccines have been developed with moderate success, often hampered by lack of strong immunogenicity and complex manufacturing. BriaCell’s Bria OTS provides a solution by increasing vaccine immunogenicity and decreasing manufacturing costs while personalizing the therapy based on matching the patient’s HLA type.1.Lacher MD et al, Front Immunol. 2018 May 15;9:776 Citation Format: Miguel A. Lopez-Lago, Vikas Bhardwaj, Xiaoyi Zheng, Sagarika pachhal, Renee Cortez, Charles Wiseman, William Williams. Engineering semi-allogeneic whole cancer vaccines with enhanced immunogenicity for the treatment of advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 685.
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Bandara, Veronika, Batjargal Gundsambuu, Silvana Napoli, Stuart Mills, Emma Thompson, Lih Tan, Jade Foeng et al. "Abstract 4085: Development and in vitro validation of an LGR-5 targeting CAR-T against colorectal cancer". Cancer Research 83, n.º 7_Supplement (4 de abril de 2023): 4085. http://dx.doi.org/10.1158/1538-7445.am2023-4085.
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Abstract Chimeric antigen receptor (CAR) T cells have demonstrated robust clinical efficacy against B-cell malignancies, and rapid translation to approval for use in man has inspired the search for CAR-T cells against solid tumours. Cancer stem cells are a small population of cells within a tumour that have the capacity to self-renew, differentiate, and initiate new tumours. Cancer stem cells are known to be resistant to chemotherapy and radiotherapy and are enriched in residual disease, which allows relapse. Targeting cancer stem cells is desirable as it will reduce a tumours’ ability to generate new cells, resulting in tumour remission. Leucine-rich G protein-coupled receptor 5 (LGR5) expression is restricted to stem cell populations in several tissues in adults. In addition, LGR5 is a marker of cancer stem cells and LGR5+ cancer cells are implicated in tumour progression and metastasis. We have designed and tested a CAR targeting the extracellular domain of LGR5, and optimised gene delivery to purified human CD3+ T cells showed robust CAR expression. Having confirmed on target specificity and cytotoxicity we show antigen-specific IFNγ release against colorectal cancer (CRC) and neuroblastoma cell lines in vitro. We confirmed the specificity and safety of the LGR5 targeting CAR-T cells by testing against normal human tissues from colon, liver, kidney, lung and heart. Using optimised gene delivery and CAR-T manufacturing protocols, we generated clinical scale batches to evaluate their potency in a preclinical CRC xenograft mouse model. A protocol for clinical scale manufacture of LGR5-targeting CAR-T cells has been developed using CD3+ T cells from healthy donors and now we have successfully tested this protocol using CRC patient-derived CD3+ T cells. This protocol is GMP ready and has been tested in a GMP manufacturing facility. Using T cells from healthy donors and CRC patients we were able to generate optimal cell numbers (80-fold expansion) with high CAR expression. These CAR-T cells showed high in vitro cytotoxicity and IFNγ release when co-cultured with LGR5 expressing CRC cell line. Post expansion, CAR-T cell products expressed markers of self-renewing naïve-like and central memory phenotype and showed very low percentage of cells that were triple-positive for PD1, TIM3 and LAG3. These results suggest a CAR-T targeting LGR5 may provide long-term protection against tumour growth. Our data positions LGR5-targeting CAR-T therapy as a viable therapeutic for human metastatic colorectal cancer types with minimal off-target effects, which we now aim to test in human clinical trials. Citation Format: Veronika Bandara, Batjargal Gundsambuu, Silvana Napoli, Stuart Mills, Emma Thompson, Lih Tan, Jade Foeng, Dylan McPeake, Timona Tylis, Caitlin Abbott, Allison Cowin, Claudine Bonder, Timothy Sadlon, Shaun McColl, Simon C. Barry. Development and in vitro validation of an LGR-5 targeting CAR-T against colorectal cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4085.
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Hankey, Kim G., Tim Luetkens, Stephanie Avila, John McLenithan, John Braxton, Karen Underwood, Clarissa Saba et al. "Eight-Day Point of Care CAR T-Cell Manufacturing on Clinimacs Prodigy from Healthy Donors As a Proof-of-Concept Study". Blood 138, Supplement 1 (5 de novembro de 2021): 2851. http://dx.doi.org/10.1182/blood-2021-154013.
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Abstract Introduction Chimeric Antigen Receptor (CAR) T-cell therapy has emerged as a powerful immunotherapy for various forms of cancer, especially hematologic malignancies. However, several factors limit use of CAR T-cells to a wider number of patients. Long manufacturing time (usually 3-4 weeks with standard of care products) poses a big challenge in treating these chemorefractory patients in a timely fashion. Thus, we evaluated the feasibility of a fresh in and fresh out, short, eight-day manufacturing process performed locally to expedite CAR T-cell drug product delivery. Herein we report the results of two experimental runs using this modified short eight-day culture process. Methods We used the CliniMACS Prodigy® closed manufacturing system and modified the 12-day T Cell Transduction (TCT) activity matrix protocol to produce anti-CD19 CAR T-cells in eight days. Normal donor mononuclear cells were collected by leukapheresis and enriched for CD4 and CD8 cells by immunomagnetic bead selection in three stages. Enriched T-cells were activated with MACS GMP T Cell TransACT and cultured at 37°C with 5% CO 2 for 16-24 hours in media supplemented with 12.5mcg/L each of IL-7 and IL-15, and 3% heat-inactivated human AB serum. On day 1 of the process, activated T-cells were transduced with lentiviral vector encoding the anti-CD19 CAR (Lentigen, LTG1563) at a multiplicity of infection (MOI) of 7-10. On day 3, the cells were washed twice and the media volume adjusted to feed the expanding cells. The culture was again fed on day 5 by exchanging half the volume of spent media with fresh supplemented media. Media supplemented with cytokines alone was used for the remaining four washes on day 6, 7 and 8. Transduction efficiency and T-cell subset frequencies were assessed by flow cytometry on the MACSQuant-10 and CAR-T Express Mode package on days 3, 6 and 8. Subsequently, we performed ELISPOT assay for CAR T-cell potency testing and in-vivo efficacy testing in NSG mice bearing Raji B cell lymphoma. Results Refer to Table 1 for details on cell populations of interest for experiment number 1 and 2. The total number of CD3 T-Cells increased from 97% on day 0 to >99.5% on the harvest day (day 8). CD3 T-cells expanded 11.6- and 34.2-fold on day 8 when compared to day 0. Transduction efficiency of ~40% was observed in both experimental runs. Final CD19 CAR T-cells numbers ranged from 9.3-13.3 x 10e8 with viability of CD3+ cells >93% for both the runs. Day 3 of the culture is an important day since a clinical decision to proceed with lymphodepletion must be made to facilitate the fresh in and fresh out approach. Here we observed reliable transduction of T-cells on day 3 with an average efficiency of 15.9%. Day 3 data reliably provided information to proceed with lymphodepletion. A total of 100,000 CD19 CAR T-cells produced in experiment #1 were exposed to beads coated with CD19 protein, BCMA control protein, or T cell-activating beads coated with anti-CD3 and anti-CD28 antibodies in an ELISPOT plate. Spots in figure 1 represents individual CAR T-cells producing IFN-gamma. This novel ELISPOT assay shows high IFN-gamma by CD19 CAR T-cells in response to the target antigen or unspecific stimulation using CD3/CD28 beads. Subsequently, NSG mice received injections of 5x10e5 Raji B cell lymphoma cells stably expressing luciferase into the tail vein. One week later, 4 mice per group received individual i.v. injections of 4x10e6 CD19 CAR T-cells, 0.3x10e6 CD19 CAR T-cells, 4x10e6 mock-transduced CAR T-cells, or media. Survival curves in figure 2 represent survival of the mice after receiving the treatment with best survival seen with 4x10e6 dose. Conclusions In these experimental runs, we were able to generate CD19 CAR+ T-cells in a short eight-day manufacturing process. The final product characteristics (viability, transduction efficiency and doses) were comparable to clinical formulations. Further, point-of-care potency assay suggests high IFN-gamma production and elimination of CD19 tumor in the in vivo murine model. The point-of-care CAR T-cell production allows for shorter vein-to-vein time and offers dramatic reduction in the product cost. Lastly, the novel potency assay via ELISPOT testing allows for rapid and visual functional analysis of the CAR T-cell product. Figure 1 Figure 1. Disclosures Hardy: Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; American Gene Technologies, International: Membership on an entity's Board of Directors or advisory committees; InCyte: Membership on an entity's Board of Directors or advisory committees. Abramowski-Mock: Miltenyi Biotec: Current Employment. Mittelstaet: Miltenyi Biotec: Current Employment. Dudek: Miltenyi Biotec: Current Employment.
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Geirsson, Halldór, Thóra Árnadóttir, Sigrún Hreinsdóttir, Judicael Decriem, Peter C. LaFemina, Sigurjón Jónsson, Richard A. Bennett et al. "Overview of results from continuous GPS observations in Iceland from 1995 to 2010". Jökull 60, n.º 1 (15 de dezembro de 2010): 3–22. http://dx.doi.org/10.33799/jokull2010.60.003.
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Iceland is a natural laboratory for a variety of processes associated with crustal deformation, such as earthquakes, magmatic events, tectonic plate motions, and glacial load changes. Continuous GPS (CGPS) measurements started in Iceland in 1995, and since then data from the network have helped to shed light on many different active deformation processes. The number of CGPS sites in Iceland tripled during 2006–2008, as a result of an international collaborative effort coordinated by Icelandic scientists. By early 2010 the number of CGPS stations in Iceland had reached 64, located primarily around and within the North-American–Eurasian plate boundary zone. Since its initiation, the CGPS network has played an important role in monitoring volcanoes and seismogenic areas, most notably during the 2009–2010 Eyjafjallajökull volcano unrest. Plate spreading of up to 2 cm per year usually dominates the horizontal motion observed at the CGPS sites, while uplift is observed at many of the stations due to recent retreat of the Icelandic ice caps. Co-seismic and post-seismic deformation of the largest earthquakes in 2000 and 2008 in the South Iceland Seismic Zone were captured by the network, and high-rate (1 Hz) CGPS observations helped to identify two magnitude 6 mainshocks in 2008 that were separated in time by only 2–3 seconds. The CGPS network has thus enabled us to monitor deformation occurring over days to months caused by migration of magma or fluids, post-seismic transients, rapid deformation caused by earthquakes and eruptions, as well as the long term plate spreading signal.
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Wang, Meng, Iulian Pruteanu, Adam D. Cohen, Alfred L. Garfall, Michael C. Milone, Lifeng Tian, Vanessa E. Gonzalez et al. "Identification and Validation of Predictive Biomarkers to CD19- and BCMA-Specific CAR T-Cell Responses in CAR T-Cell Precursors". Blood 134, Supplement_1 (13 de novembro de 2019): 622. http://dx.doi.org/10.1182/blood-2019-122513.
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CD19-specific chimeric antigen receptor (CAR) T cell therapies have been highly effective against B cell malignancies. We previously demonstrated that differential responses to anti-CD19 CAR T cell therapy in chronic lymphocytic leukemia (CLL) are associated with early memory T cell signature in apheresed, pre-manufacturing T-cells (CAR T-cell precursors). We tested the hypothesis that the composition of CAR-T precursor cells determines clinical efficacy in adult and pediatric Acute Lymphoblastic Leukemia (ALL), Non-Hodgkin's Lymphoma (NHL), Multiple Myeloma (MM), and CLL. Apheresed T cells were engineered to express 4-1BB plus CD3-zeta-signaling CARs targeting CD19, or B cell maturation antigen (BCMA). The same 9-day manufacturing process was used for all trials. CAR T cell kinetics were monitored using a CAR gene-specific quantitative PCR assay and standard clinical response assessments were performed. Apheresed T cells from 36 CLL, 30 adult ALL, 58 pediatric ALL, 33 NHL, and 25 MM patients were immunophenotyped by flow cytometry. The CLL cohort was used to discover phenotypically distinct subpopulations associated with the two main response groups; these associations were validated in the remaining patient cohorts. Eight CD8+ T cell populations or clusters were identified using the shared-nearest-neighbor clustering method (PMID: 31178118) in the CLL cohort. T cell subsets exhibiting naive (cluster 6) or early memory (cluster 4) features were significantly enriched in responding patients, whereas an effector memory CD8 subpopulation (cluster 2) marked the non-responding patients. Mapping these clusters onto apheresed CD8+ T cells from the other four diseases showed that cluster 4 predicted response to CAR T cell therapy in NHL and myeloma but not in adult and pediatric ALL. We also examined the expression of activation-regulated molecules including HLA-DR, Ki67, and exhaustion-related molecules PD1, CTLA4, TIM3, and LAG3. A CD27+ CD8+ population expressing low level CTLA4 but none of the activation or negative regulatory molecules was significantly enriched in responding CLL patients; this cluster validated in NHL and myeloma. A similar analysis on apheresed CD4+ T cells identified an early memory population (cluster 6) enriched in CLL responders, which expresses CCR7 and CD27 but not CD45RO, CD127, CD28, or other late memory/effector molecules. However, this population did not validate in any of the other diseases. Though not statistically significant, the CD4+ clusters with the largest effect size for enrichment in responders from NHL and myeloma trials exhibited early memory T cell features and lack of HLA-DR expression, suggesting that quiescent early memory state in CD4 may also be associated with clinical responses. A separate analysis of checkpoint inhibitory receptors and activation markers in memory CD4 T cell subsets confirmed the early memory, non-activated state of this population in CLL and was validated in myeloma but none of the other diseases. In vivo activation was a shared theme in CD4+ T cells for non-responding patients as well, though these CLL-defined CD4+ apheresed T cells clusters did not significantly validate in other diseases. In summary, our data confirm and extend our predictive biomarker profile in CLL to mature B cell and plasma cell malignancies by showing that a non-cycling, non-activated early memory CD8+ T cell population in pre-manufacturing cells was validated as a biomarker in myeloma, and NHL. We also showed that responder-associated apheresed CD4+ T cells with early memory features identified in CLL after CD19 CAR T infusions are validated in myeloma after BCMA CAR T. Thus, differentiation state and in vivo activation, and potentially exhaustion, separate response groups. Our findings inform next-generation CAR T-cell manufacturing using the populations identified herein as a starting population. Disclosures Pruteanu: Novartis: Employment. Cohen:Poseida Therapeutics, Inc.: Research Funding. Garfall:Surface Oncology: Consultancy; Novartis: Research Funding; Janssen: Research Funding; Amgen: Research Funding; Tmunity: Research Funding. Milone:Novartis: Patents & Royalties: patents related to tisagenlecleucel (CTL019) and CART-BCMA; Novartis: Research Funding. Gill:Novartis: Research Funding; Tmunity: Research Funding; Carisma: Equity Ownership, Research Funding; Sensei: Consultancy; Aro: Consultancy; Fate: Consultancy. Frey:Novartis: Research Funding. Ruella:Nanostring: Consultancy, Speakers Bureau; Novartis: Patents & Royalties: CART for cancer; AbClon: Membership on an entity's Board of Directors or advisory committees. Lacey:Novartis: Patents & Royalties: Patents related to CAR T cell biomarkers; Tmunity: Research Funding; Novartis: Research Funding. Svoboda:Merck: Research Funding; BMS: Consultancy, Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding; Celgene: Research Funding; Kite: Consultancy; Seattle Genetics: Consultancy, Research Funding; Kyowa: Consultancy; AstraZeneca: Consultancy. Chong:Tessa: Consultancy; Novartis: Consultancy; Merck: Research Funding. Fraietta:LEK Consulting: Consultancy; Cabaletta: Research Funding; Tmunity: Research Funding. Davis:Cabaletta: Research Funding; Tmunity: Research Funding. Nasta:Rafael: Research Funding; Aileron: Research Funding; Takeda/Millennium: Research Funding; Incyte: Research Funding; Roche/Genentech: Research Funding; Merck: Consultancy; Atara: Research Funding; Debiopharm: Research Funding. Levine:CRC Oncology: Consultancy; Vycellix: Membership on an entity's Board of Directors or advisory committees; Tmunity Therapeutics: Equity Ownership; Novartis: Consultancy, Patents & Royalties, Research Funding; Cure Genetics: Consultancy; Avectas: Membership on an entity's Board of Directors or advisory committees; Brammer Bio: Membership on an entity's Board of Directors or advisory committees; Incysus: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy. Maude:Kite: Consultancy; Novartis: Consultancy. Schuster:Nordic Nanovector: Honoraria; Pfizer: Honoraria; AstraZeneca: Honoraria; Pharmacyclics: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Loxo Oncology: Honoraria; Merck: Honoraria, Research Funding; Acerta: Honoraria, Research Funding; Novartis: Honoraria, Patents & Royalties: Combination Therapies of CAR and PD-1 Inhibitors with royalties paid to Novartis, Research Funding; AbbVie: Honoraria, Research Funding; Gilead: Honoraria, Research Funding. Stadtmauer:Celgene: Consultancy; Tmunity: Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Abbvie: Research Funding. Grupp:Novartis: Consultancy, Research Funding; Roche: Consultancy; GSK: Consultancy; Cure Genetics: Consultancy; Humanigen: Consultancy; CBMG: Consultancy; Novartis: Research Funding; Kite: Research Funding; Servier: Research Funding; Jazz: Other: study steering committees or scientific advisory boards; Adaptimmune: Other: study steering committees or scientific advisory boards. Porter:Incyte: Membership on an entity's Board of Directors or advisory committees; American Board of Internal Medicine: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Glenmark Pharm: Membership on an entity's Board of Directors or advisory committees; Immunovative: Membership on an entity's Board of Directors or advisory committees; Genentech: Employment; Wiley and Sons: Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. June:Novartis: Research Funding; Tmunity: Other: scientific founder, for which he has founders stock but no income, Patents & Royalties. Melenhorst:Novartis: Research Funding, Speakers Bureau; Parker Institute for Cancer Immunotherapy: Research Funding; Stand Up to Cancer: Research Funding; Incyte: Research Funding; IASO Biotherapeutics, Co: Consultancy; Simcere of America, Inc: Consultancy; Shanghai Unicar Therapy, Co: Consultancy; Colorado Clinical and Translational Sciences Institute: Membership on an entity's Board of Directors or advisory committees; Genentech: Speakers Bureau; National Institutes of Health: Research Funding.
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Barker, Jeremy. "(Europe Section Alessandro Volta Award) The Journey Towards the Large-Scale Commercialization of Low-Cost and High Energy Density Na-ion Batteries". ECS Meeting Abstracts MA2022-02, n.º 6 (9 de outubro de 2022): 2494. http://dx.doi.org/10.1149/ma2022-0262494mtgabs.
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Na-ion batteries based on non-aqueous electrolytes represent an inexpensive and sustainable alternative to their Li-ion counterparts [1,2]. The cost advantage is particularly apparent at the present time as the prices of battery grade Li and Co precursor salts have spiraled upwards in the last 18 months. Faradion Limited is a UK-based company, founded in 2011 and from December 2021, part of Reliance Industries Limited of India*. It is commercializing its Na-ion battery technology in a number of large format applications. It has identified and developed a wide range of inexpensive and proprietary active materials and non-aqueous electrolyte systems which offer low manufacturing costs as well as outstanding electrochemical performance and intrinsic safety. Over the past 10 years the company has incorporated these materials into full-scale Na-ion cells to a point where battery performance characteristics such as energy density, rate capability and cycle life are competitive with commercial Li-ion technologies. The Faradion Na-ion prototype cells demonstrate low-capacity fade on cycling, coupled to low polarization and excellent columbic and energy (round-trip) efficiency and may be configured for both energy and power applications. The use of Al for both current collectors serves as an additional and significant cost and safety benefit and allows the cells to be stored and transported at 0 V (i.e. physically shorted) [3]. The Faradion Na-ion cells are manufactured on commercial Li-ion production lines using proven battery designs [4,5]. Pouch, cylindrical and prismatic cell designs have all been demonstrated successfully [6]. Faradion has worked with its commercial partners to scale-up its Na-ion cell chemistry to the 40 Wh and 90 Wh pouch cell level – see for example, figure 1. These cells deliver a cell level specific energy of over 150 Wh/kg and have been incorporated into a range of demonstrator energy storage applications, including E-bike, residential, renewables, telecoms and automotive [6]. Faradion’s technology roadmap indicates that a specific energy in excess of 190 Wh/kg will be accessible in the near future. Other key attributes such as low precursor costs, material sustainability and excellent temperature range, confirm that Faradion’s Na-ion battery technology will prove commercially successful in a range of large format applications [7]. Reference s: [1] J. Barker, M.Y. Saidi and J. Swoyer, Electrochem. Solid-State Chem. 6 (2003) A1 [2] K. Kubota and S. Komaba, J. Electrochem. Soc., 162 (2015) A2538. doi.org/10.1149/2.0151514jes [3] (a) A. Rudola, C.J. Wright and J. Barker, Energy Materials Advances, 2021 Article ID 9798460. doi.org/10.34133/2021/9798460 (b) J. Barker and C.J. Wright, Assignee: Faradion Limited. US Patent #11159027 [4] A. Bauer, J. Song, S. Vail, W. Pan, J. Barker and Y. Lu, Adv. Energy Materials, 1 2018, 1702869. doi.org/10.1002/aenm.201702869 [5] For example, J. Barker and R.J. Heap, Assignee: Faradion Limited, US Patent#9774035, US Patent #9917307, US Patent #1019628, US Patent #10115966, US Patent #10050271, US Patent #10399863 [6] (a) American Chemical Society, Chemical & Engineering News, July 20, 2015, Vol. 93, Issue 29. (b) American Chemical Society, Chemical & Engineering News, May 24, 2022, Vol. 100, Issue 19 [7] A. Rudola et al. J. Mater Chem A, 2021, 9, 8279-8302. doi.org/10.1039/D1TA00376C Footnote: [*] In late 2021, Faradion Limited was acquired by Reliance New Energy Systems Limited (RNESL), a wholly owned subsidiary of Reliance Industries Limited (RIL) of India. Figure 1
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Assi, Rita, Nabil Hagag, Sherif Farag, Robert V. B. Emmons, Allie Carter, Magdalena Czader, Rafat Abonour, Lionel Apetoh, Yupo Ma e Huda S. Salman. "Phase I First-in-Human Study on the Feasibility, Safety, and Antitumor Activity of CD4-Redirected Chimeric Antigen Receptor (CAR) T-Cell Therapy in Patients with CD4+ T-Cell Malignancies (TCM)". Blood 142, Supplement 1 (28 de novembro de 2023): 6854. http://dx.doi.org/10.1182/blood-2023-180111.
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Background TCM are aggressive diseases with poor outcomes. Translating the CAR T-cell therapy success from B-cell diseases to TCM has proven challenging. CD4 is an attractive therapeutic target, owing to its restricted expression on normal tissues. In this first-in-human phase I study, we investigate the autologous third generation CD4-redirected CAR T-cell safety, tolerability, manufacturing feasibility, trafficking and preliminary efficacy in patients with R/R CD4+ TCM who failed standard therapies. Methods The investigational construct is engineered with a single-chain variable fragment (ScFV) and dual co-stimulators (CD28; 4-1BB), fused to CD3zeta and CD8 leader sequence, packaged in lentivirus and transducer into T-cells. Patients received conditioning therapy with fludarabine and cyclophosphamide. CD4CAR product is administered in a 3+3 dose-escalation scheme. Dose-limiting toxicities (DLT) were monitored during the initial 42-days post-treatment. Treatment-emergent adverse events (AE) were graded by CTCAE v5.0 Results Three patients with median age of 63 years (range, 18-68) were enrolled and treated at DL1 (2.0x10^5/kg), including 2 (66%) women and 2 (66%) African-American. Median number of prior therapies was 3 (range, 2-4) (Figure). AEs included grade 3-4 hematologic toxicity in 3 (100%) patients, all present before enrollment. There was no protocol defined DLTs. All grade ≥3 lymphopenia reverted to grade 2 by day 30 and no related infections occurred between CAR infusion and hematopoietic stem cell transplantation (HSCT). Since infusion, the CAR T-cells percentage in peripheral blood had continued to expand. CD4CAR T-cells were detectable in all patients for at least 28 days post-infusion, meeting the primary endpoint, and on D111 in one patient. CD4CAR expansion was reflected on by a decrease in CD4/CD8 ratio and flow cytometry using ScFV Fab2 specific antibodies (Figure). Cytokine response analysis CD4CAR was associated with variable but significant production that seems to correlate with clinical responses (Figure; More data at meeting). No cytokine-mediated organ toxicities were observed. Bone marrow and peripheral blood flow cytometry confirmed complete remission (CR) in 2 patients at day 30 (PTCL and T-ALL). Patient 3 (mycosis fungoides) achieved hematological CR with stable skin lesions. Post-treatment day 30 skin biopsy demonstrated persistent disease with marked loss of CD4. Conclusions CD4CAR T-cell therapy is feasible in patients with R/R CD4+ TCM. 2/3 patients achieved CR and the third achieved hematological CR with stable skin disease. Toxicities were manageable without DLT upon completion of cohort 1. The cytokine response suggests immune activation and tumor recognition by CD4CAR T-cells. Dose escalation will proceed. NCT03829540
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Clarke, Samuel, R. Geczy, A. Balgi, S. Park, R. Zhao, M. Swaminathan, R. Tieu et al. "Abstract 1785: Multi-step engineering of gene-edited CAR T cells using RNA lipid nanoparticles". Cancer Research 83, n.º 7_Supplement (4 de abril de 2023): 1785. http://dx.doi.org/10.1158/1538-7445.am2023-1785.
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Abstract Autologous chimeric antigen receptor (CAR) T therapies utilize patient cells and can be limited by cell quality, and the high manufacturing burden of viral vectors. As such, there is a need for allogeneic, “off-the-shelf” CAR T cells to make these transformative treatments widely available. However, allogeneic therapies require multiple genetic engineering steps to express CAR and to delete proteins responsible for graft-versus-host disease. Messenger RNA (mRNA) is a promising approach for expression of therapeutic proteins and gene editing nucleases. In this work, we demonstrate a new method for multi-step engineering of gene-edited CAR T cells using RNA lipid nanoparticles (LNPs). LNPs encapsulating Spy-Cas9 mRNA, TCR and CD52 guide RNA (sgRNA), and CAR mRNA were produced using microfluidics. The CAR construct contained an anti-CD19 scFv binding domain and CD3ζ/4-1BB co-stimulatory domains. Microgram quantities of RNA LNPs were produced to optimize LNP packaging, cargo ratios, and sgRNA combinations. Lead candidates were scaled to milligrams. Purified human primary T cells were cultured, activated, and expanded in serum-free media in plates, flasks and bioreactors. CAR+, TCR− or CD52− cells were generated by addition of the corresponding LNP to activated cells. Cytotoxic killing was determined by co-culture assays with leukemia cells. Gene knockout, CAR expression, viability and cell killing were measured using flow-cytometry. CD19 CAR was selected as a relevant protein for expression, with TCR and CD52 proteins as gene knockout targets. Single-step addition of CAR LNPs to T cells resulted in transfection efficiencies of 95.0 ± 2.1% and high protein expression. Upon TCR or CD52 LNP addition to T cells, the onset of gene editing was within 48 hours, reaching single target knockout efficiencies of 92.3 ± 3.0% (TCR−), and double knockouts (TCR−/CD52−) of 74.5 ± 6.1%. Similar results were obtained when comparing different LNP batch sizes (microgram to milligram RNA) and cell culture vessels (125,000 to 45 million cells), demonstrating scalability of both the LNP production and cell treatment. Cell viabilities above 90% were maintained at all steps and for all RNA LNPs. Finally, as proof-of-concept for multi-step engineering, sequential addition of TCR LNPs and CAR LNPs resulted in simultaneous CAR expression and TCR gene knockout. These “off-the-shelf” gene-edited CAR T cells were functionally equivalent to non-edited cells in a B cell killing assay, efficiently clearing over 80% of leukemia target cells at a 1:1 ratio. Our findings demonstrate the advantages of LNPs for RNA delivery to T cells. The simple and gentle nature of LNP cell treatment allows for multiple genetic engineering steps for simultaneous expression and deletion of proteins. Furthermore, LNPs can be easily manufactured using microfluidics, enabling small-scale screening of RNA libraries and rapid scale-up of lead candidates for clinical translation. Citation Format: Samuel Clarke, R Geczy, A Balgi, S Park, R Zhao, M Swaminathan, R Tieu, N Hoang, C Webb, E Watt, M Wong, M Fujisawa, N Jain, Angela Zhang, Anitha Thomas. Multi-step engineering of gene-edited CAR T cells using RNA lipid nanoparticles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1785.
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Wang, Wei (Vivian), Jing Li, Lin Ma, Man Xu e Qun Yin. "Abstract LB043: VBC101-F11: An innovative EGFR/cMet bispecific antibody drug conjugate (ADC) targeting key oncogenic drivers in solid tumors". Cancer Research 84, n.º 7_Supplement (5 de abril de 2024): LB043. http://dx.doi.org/10.1158/1538-7445.am2024-lb043.
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Abstract EGFR and cMet are two classic growth factor receptors frequently co-expressed in solid tumors at significantly high levels, while only limited to moderate expression in normal tissues. Beyond their co-expression patten, the aberrant or over expression in their pathway are implicated in oncogenesis. Notably, MET pathway activation either through increased cMet expression or its ligand, is often associated with resistance to EGFR tyrosine kinase inhibitors (TKI). Therefore, the interplay between EGFR and cMet, coupled with their differential expression in tumors versus normal tissue substantiates the rationale for a bispecific approach that targets both receptors to enhance tumor specificity. VBC101-F11 is a bispecific anti-EGFR/cMet ADC engineered to deliver clinically validated cytotoxic agents to tumor cells with a drug-to antibody ratio (DAR) of 4. This innovative design distinguishes VBC101-F11 from other EGFR/cMet-targeting agents on the market or in clinical trials (ABBV399 or AZD9592), optimizing both efficacy and safety. 1. VBC101-F11 features a low-affinity EGFR arm coupled with a high-affinity cMet arm. Incorporating the low-affinity EGFR arm enhances binding avidity and internalization, resulting in a superior cytotoxicity with a 5-fold improvement in IC50 compared to ABBV-399 (targeting cMet only). This nuanced EGFR arm design ensures a reduction in EGFR-related off-target toxicity in normal tissues. 2. The biparatopic design in cMet arm further underscores our strategic rationale by demonstrating a synergistic effect in terms of binding, internalization, and functional blocking with a 10-fold improvement in EC50 compared to the monospecific parental antibodies that target a single epitope. This ensures VBC101-F11’s maximized efficacy in tumor cells. 3. VBC101-F11’s innovative nanobody-based format sets our molecule apart. Living imaging data in mouse model reveals that VBC101-F11 (90kD) achieves superior tumor penetration and accumulation from 1 hour to over 90 hours surpassing the mAb ABBV399 and bispecific antibody AZD9592, both at 150kD. 4. VBC101-F11 has demonstrated outstanding molecular developability in stress tests, particularly in human and non-human primate (NHP) plasma, where both the antibody component and the entire ADC molecule exhibit remarkable stability, positioning VBC101-F11 as a viable candidate for future Chemistry, Manufacturing, and Controls (CMC) development. 5. In in vivo CDX models using various lung cancer cell lines, VBC101-F11 equipped with MMAE warhead displayed a marked superiority in tumor growth inhibition (TGI of 60% vs. 17%) at a single dose of 3mg/kg compared to MMAE conjugating ADC ABBV-399. Further payload exploration, such as DNA replication inhibitor, has also yielded promising results, with VBC101-F11-new payload showing comparable efficacy to the same class ADC AZD9592 in models with low EGFR and high cMet expression (100% TGI) and in those with moderate EGFR/cMet expression (~ 60% TGI). In summary, VBC101-F11, with unique design and distinguished attributes, has demonstrated its remarkable potential in the landscape of anti-EGFR/cMet therapies. The encouraging efficacy observed in preclinical models supports the molecule’s advancement into clinical development, positioning it as a best-in-class bispecific ADC for treating tumors in patients. Citation Format: Wei (Vivian) Wang, Jing Li, Lin Ma, Man Xu, Qun Yin. VBC101-F11: An innovative EGFR/cMet bispecific antibody drug conjugate (ADC) targeting key oncogenic drivers in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB043.
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Osbora, Alan J. "Eye of the Needle: Cold Stress, Clothing, and Sewing Technology During the Younger Dryas Cold Event in North America". American Antiquity 79, n.º 1 (janeiro de 2014): 45–68. http://dx.doi.org/10.7183/0002-7316.79.1.45.
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AbstractThis paper examines the possible underlying systemic contexts) for spurred flake gravers and eyed bone needles recovered from Paleoindian sites in North America. The idea that spurred flake gravers and eyed bone needles were closely associated is not new. Archaeologists in both Eurasia and North America have also proposed that eyed bone and ivory needles were used for manufacturing tailored skin clothing. It is suggested here that spurred flake gravers and eyed bone needles may, in fact, be the material correlates of critical non-subsistence related work carried out by women to meet the challenges of very severe winters and cold stress of the Younger Dryas Cold Event (YDCE) between 12,900–11,600 cal. B.P. It is argued here that such expediently produced flake implements and curated sewing technology including eyed needles ultimately reflect the significant ecological bottlenecks) posed by the YDCE for Paleoindian populations. Metric attributes of both spurred flake gravers and eyed bone needles, their spatial co-occurrence in archaeological contexts, and their temporal co-occurrence within the YDCE lend empirical support for this causal argument.
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Hooper, Glenn. "Furnishing Scotland and the World: Morris & Co., Glasgow, 1945–65". Journal of Scottish Historical Studies 37, n.º 1 (maio de 2017): 52–72. http://dx.doi.org/10.3366/jshs.2017.0202.
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Although many British furniture manufacturers were increasingly aware of design innovation throughout the 1930s, and several even began to employ simpler forms and produce items in steel or plywood, the majority remained faithful to conservative styles. Efforts to educate the public about modern design went some way towards introducing greater levels of understanding – among producers and consumers both – but for many it was easier to play safe and continue along well-worn paths. During the post-war years, when a break with tradition and a culture more open to the Scandinavian aesthetic tentatively developed, the Glasgow firm Morris & Co. were one of those who embraced most fully these new ideas and who made a significant contribution to design innovation. Drawing business and design history together, this article discusses the ways in which the company championed the contemporary styles emanating from Europe and North America, how it positioned itself within the wider British manufacturing industry, and the ways in which its director, Neil Morris, envisaged for both his products and his firm a truly global reputation.
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Herrera, Pablo C., Cristina Dreifuss-Serrano e Benito Juarez. "Design during COVID-19: agents and allies in the role of designer, digital fabrication and distributed production". Strategic Design Research Journal 14, n.º 1 (9 de abril de 2021): 236–51. http://dx.doi.org/10.4013/sdrj.2021.141.20.
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During COVID-19 global emergency, designers proposed solutions at different scales, as quick responses to demands from different agents. In the same way, we critically analyzed the emergence of allies, protocols and tools, which allowed the optimization of fabrication, from traditional manufacturing into distributed co-production. The analyzed local networks produced global co-design experiences, with involvement of FabLabs and users from different disciplines. Through case studies and the evaluation of surveys and testimonials from users and makers, we analyze the global panorama, to finally explore the specific situation in Latin America. This establishes a relationship between medical demand and digital fabrication, which allows evidence of positive and negative situations to be consider as new, significant aspects for the design in the future. The leading role acquired by the ecosystem surrounding digital fabrication during the pandemic, could enhance its processes in the search for greater positioning, changing society from within the different communities.
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Hart, Danielle K. "If Past is Prologue, then the Future is Bleak: Contracts, Covid–19, and the Changed Circumstances Doctrines". Texas A&M Law Review 9, n.º 2 (março de 2022): 347–403. http://dx.doi.org/10.37419/lr.v9.i2.2.
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At the heart of most of the systemic problems currently confronting individuals and businesses as a result of the COVID–19 pandemic is quite literally a contract. Housing. Insurance. Food. Health care. Child care. Employment. Manufacturing. Construction. Supply chains. You name it. Contracts are implicated everywhere. So make no mistake: How contract law addresses these ostensibly private contracts will have profound social consequences. If the past really is prologue, then the future is indeed bleak. The empirical study conducted for this Article establishes what the conventional wisdom has claimed for the last 70 years. More specifically, the empirical study here shows that the common law’s changed circumstances doctrines (“CCDs”)—namely, impossibility, impracticability of performance, and frustration of purpose—will generally not excuse a party from performing his obligations under a contract, regardless of the changed circumstance he alleges. Contrary to all the CCD literature that addresses this issue, this Article makes the unconventional argument that the CCDs should be more broadly available, meaning they should be more successful in excusing contract performance when triggered by catastrophic circumstances. And unlike the rest of the field, which focuses on the CCDs themselves, this Article argues that to effectively address the allocation of unforeseen risks in general and catastrophic risks like a pandemic in particular, we must reframe the legal approach to contract formation. From there, given that the solution to the changed circumstances problem preferred by courts and commentators is an explicit risk-allocation term in the parties’ contract, the solution proposed in this Article to the risk-allocation problem literally suggests itself. A risk-and-loss-allocation clause should be mandated in most contracts as a part of contract formation. The type of risk-and-loss-allocation clause and how the clause would work would depend on whether the contract is co-drafted or adhesive. Generally, the inclusion of a risk-and-loss-allocation clause would facilitate transactions and encourage contracting by ensuring that contracts remain efficient and predictable. The main difference between the risk-and-loss-allocation clause proposed here and existing contract law, of course, is who ends up bearing all the risk and loss occasioned by the catastrophic changed circumstance. To be clear, if nothing changes and our approach to contract formation remains the same as it is right now, then all of the risk and all of the attendant loss will generally be left to lie where it falls—namely, on the party trying to get out of the contract because of the changed circumstances—and this will be the result regardless of the legal theory used to justify (or demonize) the CCDs or any changes made to the doctrines themselves. But if we finally acknowledge the public aspects of contracts and contract law, namely, that they do in fact produce social consequences that extend beyond the individual contract and contracting parties, then contracts and contract law may well be part of the solutions to some of the most pressing problems currently confronting American society now and into the future.