104 research outputs found
Solid tumour cellular therapy — principles of toxicity management
No full textFollowing the Food and Drug Administration (FDA) approval of lifileucel and afami-cel for patients with advanced melanoma and synovial sarcoma, respectively, there is a need for improved understanding and guidance regarding the management of toxicity associated with adoptive cellular therapies (ACTs) for solid tumours. Further approvals are expected in coming years, with toxicity management representing a significant consideration for centres looking to implement such advanced therapy medicinal products. Importantly, first-generation tumour-infiltrating lymphocyte therapies are associated with unique toxicities compared with gene-modified T-cell therapies such as chimeric antigen receptor T-cell therapy (CAR T) and T-cell receptor-modified therapy (TCR T), presenting novel challenges for treating healthcare professionals. Extrapolating from experience with CAR T in the field of haemato-oncology, coupled with the historical use of high-dose interleukin-2 in solid tumour therapeutic regimens and more recently lifileucel and afami-cel, has led to the development of core principles for managing toxicity, which is discussed here. Looking to the future, a rapidly developing field with next-generation ACT products, a basic knowledge of such core principles will be an important foundation for healthcare professionals working in this space
What’s a Nice Girl Like You Doing With a Priest Like This? Biography, Jewish Studies, and Gentile Subjects
No full textThe author writes about her doctoral thesis, a biography of French Revolution-era Catholic priest Henir Gregoire. She discusses some of the advantages of the biographical approach to history, as well as some of the advantages to studying certain non-Jewish figures in order better to understand Jewish history.Sepinwall, Alyssa “What’s a Nice Girl Like You Doing With a Priest Like This? Biography, Jewish Studies, and Gentile Subjects,” in AJS Perspectives (Spring 2007): 30 – 32.1529-642
Replication Data for: Survey of Replication Data in AJPS, APSR, PQR, AJS, and ARP
No full textSurvey of Replication Data in AJPS (2012-2016), APSR (2012-2014), PRQ (2012-2016), AJS (2012-2014), and ARP (2012-2014)
Title, author(s), page numbers, issue and volume numbers are recorded for each article. Domestic in focus, empirical, a link to replication data, and an active (not "dead") link to replication data are all coded as 1. The links are then broken down by the type of website they link to. All links are provided
Replication Data for: Survey of Replication Data in AJPS, APSR, PQR, AJS, and ARP
No full textSurvey of Replication Data in AJPS (2012-2016), APSR (2012-2014), PRQ (2012-2016), AJS (2012-2014), and ARP (2012-2014)
Title, author(s), page numbers, issue and volume numbers are recorded for each article. Domestic in focus, empirical, a link to replication data, and an active (not "dead") link to replication data are all coded as 1. The links are then broken down by the type of website they link to. All links are provided
Immunotherapy of sarcomas with modified T cells
No full textPURPOSE OF REVIEW: To summarize the development of modified T-cell therapies in sarcomas and discuss relevant published and ongoing clinical trials to date. RECENT FINDINGS: Numerous clinical trials are underway evaluating tumor-specific chimeric antigen receptor T cells and high affinity T-cell receptor (TCR)-transduced T cells in sarcomas. Notably, translocation-dependent synovial sarcoma and myxoid/round cell liposarcoma are the subject of several phase II trials evaluating TCRs targeting cancer testis antigens New York esophageal squamous cell carcinoma-1 (NY-ESO-1) and melanoma antigen-A4 (MAGE A4), and response rates of up to 60% have been observed for NY-ESO-1 directed, modified T cells in synovial sarcoma. Challenges posed by modified T-cell therapy include limitations conferred by HLA-restriction, non-immunogenic tumor microenvironments (TME), aggressive lymphodepletion and immune-mediated toxicities restricting coinfusion of cytokines. SUMMARY: Cellular therapy to augment the adaptive immune response through delivery of modified T cells is an area of novel therapeutic development in sarcomas where a reliably expressed, ubiquitous target antigen can be identified. Therapeutic tools to improve the specificity, signaling, proliferation and persistence of modified TCRs and augment clinical responses through safe manipulation of the sarcoma TME will be necessary to harness the full potential of this approach
Long-term Results after Restoring Flexor Tendon Injury in Children Younger than Age 10 Years
No full textBackground: In regard to the rarity of pediatric tendon lacerations compared with the adult population, sparse knowledge exists. Published reports indicate that the incidence of “good” flexor tendon repair outcomes is low. This study aimed to determine the injury pattern and demographics of pediatric flexor tendon injuries over the past decade.Methods: A retrospective chart review of all flexor tendon injuries between 2005 and 2015 was performed. Parameters reviewed included demographics, injury mechanism, repair technique, outcomes, and complications.Results: A total of 20 patients with a median age of 4 years and 4 months experienced 45 tendon injuries. The most common cause of injury was glass (n = 10), with the most common digit injured being the index finger (n = 8). Zone II had the highest number of injuries (n = 14). The modified Kessler core and peripheral running sutures technique were used in all primary repairs (n = 18). Using author designed evaluation system, 80% of patients experienced excellent recovery. Four patients had good results. Only one patient complicated with rupture necessitating further surgery that its final evaluation was excellent.Conclusions: The outcome of restoring flexor tendon injury of children is satisfactory, and we recommend that
Benchmarking Performance of Offshore Construction Projects
No full textSince the rise of oil prices in 2007, the difference in gas prices between the US and Europe has increased steadily. The pressure to efficiently produce and maintain gas assets has thus also increased. On top of these external trends, ONEgas strives to be in the top quartile companies in the gas market. The integrated contractor of ONEgas, AJS, is stimulated to continuously improve their performance. Currently projects are evaluated separately on changing aspects. A comparison of projects based on their performance assessment is thus not reliable. This research proposes a benchmark tool for AJS to compare and signal performance. The corresponding analysis provides arguments in discussions around the performance of AJS. It was found that performance can be monitored by using the Project Management Triangle and controlled by acting on the comparison of the different projects with regard to the size of a project. The Project Management Triangle consists of Cost, Schedule, Scope and Quality as universal performance indicators. It is used to ensure comparability among projects in the Benchmark. The provided method for the selection of appropriate data can be used for the creation of a benchmark of other (unrelated) projects. The AJS benchmark is created in such a way that time, effort and required knowledge are reduced to a minimum. The required data is however only available after the project has completely been finished. It is therefore advised to incorporate the benchmark as one of the very last actions in the close out process. When monitoring and acting on the measured and compared performance it is important to keep the seven paradoxes in mind. When these are disregarded the action may very well have the opposite effect. It is thus advised to only use the benchmark as a signaling tool and have a separate study on how to improve a specific situation.SEPAMPOLGTechnology, Policy and Managemen
Adherens junctions organize size-selective proteolytic hotspots critical for Notch signalling
No full text© 2022, The Author(s), under exclusive licence to Springer Nature Limited.Adherens junctions (AJs) create spatially, chemically and mechanically discrete microdomains at cellular interfaces. Here, using a mechanogenetic platform that generates artificial AJs with controlled protein localization, clustering and mechanical loading, we find that AJs also organize proteolytic hotspots for γ-secretase with a spatially regulated substrate selectivity that is critical in the processing of Notch and other transmembrane proteins. Membrane microdomains outside of AJs exclusively organize Notch ligand–receptor engagement (LRE microdomains) to initiate receptor activation. Conversely, membrane microdomains within AJs exclusively serve to coordinate regulated intramembrane proteolysis (RIP microdomains). They do so by concentrating γ-secretase and primed receptors while excluding full-length Notch. AJs induce these functionally distinct microdomains by means of lipid-dependent γ-secretase recruitment and size-dependent protein segregation. By excluding full-length Notch from RIP microdomains, AJs prevent inappropriate enzyme–substrate interactions and suppress spurious Notch activation. Ligand-induced ectodomain shedding eliminates size-dependent segregation, releasing Notch to translocate into AJs for processing by γ-secretase. This mechanism directs radial differentiation of ventricular zone-neural progenitor cells in vivo and more broadly regulates the proteolysis of other large cell-surface receptors such as amyloid precursor protein. These findings suggest an unprecedented role of AJs in creating size-selective spatial switches that choreograph γ-secretase processing of multiple transmembrane proteins regulating development, homeostasis and disease.11Nsciescopu
Marrow-Infiltrating Regulatory T Cells Correlate with the Presence of Dysfunctional CD4+PD-1+ Cells and Inferior Survival in Patients with Newly Diagnosed Multiple Myeloma.
No full textPURPOSE: Immune dysregulation is described in multiple myeloma. While preclinical models suggest a role for altered T-cell immunity in disease progression, the contribution of immune dysfunction to clinical outcomes remains unclear. We aimed to characterize marrow-infiltrating T cells in newly diagnosed patients and explore associations with outcomes of first-line therapy. EXPERIMENTAL DESIGN: We undertook detailed characterization of T cells from bone marrow (BM) samples, focusing on immune checkpoints and features of immune dysfunction, correlating with clinical features and progression-free survival. RESULTS: We found that patients with multiple myeloma had greater abundance of BM regulatory T cells (Tregs) which, in turn, expressed higher levels of the activation marker CD25 compared with healthy donors. Patients with higher frequencies of Tregs had shorter PFS and a distinct Treg immune checkpoint profile (increased PD-1, LAG-3) compared with patients with lower frequencies of Tregs. Analysis of CD4 and CD8 effectors revealed that low CD4effector (CD4eff):Treg ratio and increased frequency of PD-1-expressing CD4eff cells were independent predictors of early relapse over and above conventional risk factors, such as genetic risk and depth of response. Ex vivo functional analysis and RNA sequencing revealed that CD4 and CD8 cells from patients with greater abundance of CD4effPD-1+ cells displayed transcriptional and secretory features of dysfunction. CONCLUSIONS: BM-infiltrating T-cell subsets, specifically Tregs and PD-1-expressing CD4 effectors, negatively influence clinical outcomes in newly diagnosed patients. Pending confirmation in larger cohorts and further mechanistic work, these immune parameters may inform new risk models, and present potential targets for immunotherapeutic strategies
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