CD70 and its ligand, CD27, have been described as both activating and suppressing for different cell types including B and T cells. There has been speculation that the CD70/CD27 axis can act in a checkpoint or co-stimulatory manner in certain immuno-oncology settings. Knockout (KO) of CD70 function scored highly in a CRISPR/Cas9 screen of candidate genes for enhanced T cell activity. Deletion of other checkpoint candidates such as PD1, TIM3, LAG3 and TIGIT scored much lower than CD70, both alone and in combination with each other. T cells with CD70 KO showed resistance to exhaustion upon repeated stimulation in culture. CAR-T cells with CD70 KO similarly showed exhaustion resistance, as well as a reduction in apoptosis, increased proliferation, and improved target cell lysis upon sequential rechallenges. CTX130 is an investigational allogeneic CAR-T therapy currently being studied in patients with CD70-expressing tumors, including clear cell renal cell carcinoma and B and T cell malignancies. CTX130 contains KOs of TRAC to avoid GvHD, B2M to protect the product from patient T cells, and CD70 for enhanced CAR-T performance. Comparing CTX130 with and without CD70 KOs shows that CAR-T cells with CD70 KO have increased potency, enhanced ability to withstand multiple tumor challenges in vivo, and increased resistance to overexpression of PDL1 on target cells. Interestingly, while CD70 surface expression may be extremely low or undetectable after manufacturing of CD70-targeted CAR-T cells without CD70 KO, the beneficial properties outlined here are only achievable when the CD70 gene is genetically knocked out. In summary, KO of CD70 confers benefit to CAR-T cells that far exceeds KO of other checkpoint related genes, and this benefit was present regardless of the antigen being targeted. CD70 KO is included in the CTX130 investigational allogeneic CAR-T therapy currently in clinical trials. Citation Format: Mary-Lee Dequeant, Jason Sagert, Demetri Kalaitzidis, Hui Yu, Ashley Porras, Brigid McEwan, Zinkal Padalia, Paul Tetteh, Thao Nguyen, Andrew Dunn, Sarah Spencer, Nicolette Lee, Henia Dar, Daniel Henderson, Sushant Karnik, Pooja Keerthipati, Jonathan A. Terrett. CD70 knockout: A novel approach to augment CAR-T cell function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1537.
System models are commonly used in tertiary education as a mechanism for describing the interacting components of educational phenomena, but have hitherto been uncritically accepted. This paper provides a critical review of existing systems models, including the 3P model defined Biggs, and outlines their conceptual challenges. A revised model developed for curriculum research is presented. The paper would be of interest to those undertaking educationfocused research, scholarly teaching practitioners as well as those with an interest in the use of systems models as a framework for educational alignment. IntroductionEducational phenomena are characterised by enormous complexity in both the number of variables and the dynamic nature of their interaction over time. Navigation of this complexity when developing a research design is a difficult task, especially for the novice educational researcher or scholarly practitioner. In particular, identifying the boundaries of a topic for study and the connections between the multiple influences on educational events or outcomes can seem a daunting and unachievable task.Systems-based models have commonly been used as a means of managing data for educational phenomena as a topic of research or for improved practice (Biggs 1999;Doll 2008;Frederiksen 1989;Hicks 2007;Iannone 1995;Semetsky 2008). As a social system with multiple complex parts in constant flux and interaction with the environment, education epitomises the characteristics of a complex system (Hicks 2007). Systems models have been advanced to assist research and development relating to various aspects of learning and teaching, including curriculum design. In their paper on the application of systems theory as a conceptual framework in curriculum development, Chen and Stroup (1993) argue that systems approaches have great potential for the development of coherent explanations for educational events. They characterise some of the major strengths of systems approaches for education as:
Category: Diabetes, Midfoot/Forefoot Introduction/Purpose: Most diabetic foot ulcer (DFU) patients have peripheral neuropathy (PN), which presents with numbness, pain and weakness. DFU patient’s perceived pain and other clinical factors affecting their pain level have not been reported. Although high prevalence of depression among diabetes patients have been reported, its correlation with perception of pain has not been investigated in patients with ulcers. PROMIS (Patient-Reported Outcomes Measurement Information System) allows accurate quantification of patient’s physical function (PF), pain interference (PI) and Depression. We aimed to investigate 1) if DFU patient’s pre- and postoperative pain level correlate with demographic data/ laboratory values/surgical procedure and 2) if depression level and/or surgical intervention impacts pain. Methods: Prospectively collected PROMIS (PF, PI, D) assessments were obtained for patients who underwent surgical intervention for infected DFU between February 2015 and November 2018 (n=240). Patients who had at least 3 consecutive visits with a minimum follow up of 3 months and had completed all assessments for each visit were included (n=92). Demographic data, BMI, medical comorbidities, Hemoglobin A1C (A1C), procedure performed, wound healing status, PN, depression, and amputation level were collected. The mean follow-up duration was 4.7 (3-12) months. T-score distribution of initial PROMIS scores were calculated and compared to the US population. Chi-Square test and Minimum clinically important differences (MCID) were calculated to assess the co-occurrence of different PROMIS domains. We also analyzed other clinical factors and their influences on MCID changes in PROMIS domains. Results: The 92 patients were 80.4% male (n=74) and had an average age of 60.5 (33-96) and BMI of 34.1 (22.0-57.5). Irrigation and debridement (n=39), forefoot amputations (n=46), mid/hindfoot amputations (n=14) and Syme or above amputations (n=12) were performed. Mean pre-operative PF, PI, and depression PROMIS scores were 34.4, 58.7, and 51.4, respectively. Average scores at final follow up increased 1.7, decreased 0.1, and increased 0.2, respectively. Depression and PI were the most strongly associated co-occurrences (p=0.03) pre-operatively and remained significant (p<0.01) with respect to post-operative MCID. PF and PI also strongly co-occurred pre-operatively (p=0.04) and with post-operative MCID assessment (p=0.02). PF was affected by initial A1C (p=0.03) and wound healing status (p=0.03). PN was the only clinical factor found to affect PI (p=0.03). Conclusion: DFU patients with PN experience a significant amount of pain. Contrary to previous studies, we did not find a higher prevalence of depression in our DFU cohort compared to the average United States population. The study results do not indicate the origin of pain, which can be further investigated using other measures, such as PROMIS Neuropathic Pain Quality Scale. Surgical intervention did not significantly relieve pain in DFU patients. These findings may be referenced for pre-operative patient education and setting expectation for surgery.
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