Genetically modified T cells expressing chimeric antigen receptors (CARs) demonstrate robust responses against lineage restricted, non-essential targets in hematologic cancers. However, in solid ...tumors, the full potential of CAR T cell therapy is limited by the availability of cell surface antigens with sufficient cancer-specific expression. The majority of CAR targets have been normal self-antigens on dispensable hematopoietic tissues or overexpressed shared antigens. Here, we established that abnormal self-antigens can serve as targets for tumor rejection. We developed a CAR that recognized cancer-associated Tn glycoform of MUC1, a neoantigen expressed in a variety of cancers. Anti-Tn-MUC1 CAR T cells demonstrated target-specific cytotoxicity and successfully controlled tumor growth in xenograft models of T cell leukemia and pancreatic cancer. These findings demonstrate the therapeutic efficacy of CAR T cells directed against Tn-MUC1 and present aberrantly glycosylated antigens as a novel class of targets for tumor therapy with engineered T cells.
•Cancer cells of many tissues express an abnormal glycoform of MUC1, Tn-MUC1•Normal human tissue does not express detectable Tn-MUC1 on the cellular surface•CAR T cells are engineered to target Tn-MUC1 lyse tumor cells in vitro and in vivo•Abnormal glycoform epitopes are valid clinical targets for CAR T cells
Posey and colleagues developed a CAR T cell therapy to break immune tolerance to solid tumors by targeting an aberrantly glycosylated, cancer-specific glycoprotein in multiple cancer histotypes and demonstrated efficacy and safety in tumors as diverse as leukemia and pancreatic cancer.
In the phase 1-2 portion of an adaptive trial, REGEN-COV, a combination of the monoclonal antibodies casirivimab and imdevimab, reduced the viral load and number of medical visits in patients with ...coronavirus disease 2019 (Covid-19). REGEN-COV has activity in vitro against current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern.
In the phase 3 portion of an adaptive trial, we randomly assigned outpatients with Covid-19 and risk factors for severe disease to receive various doses of intravenous REGEN-COV or placebo. Patients were followed through day 29. A prespecified hierarchical analysis was used to assess the end points of hospitalization or death and the time to resolution of symptoms. Safety was also evaluated.
Covid-19-related hospitalization or death from any cause occurred in 18 of 1355 patients in the REGEN-COV 2400-mg group (1.3%) and in 62 of 1341 patients in the placebo group who underwent randomization concurrently (4.6%) (relative risk reduction 1 minus the relative risk, 71.3%; P<0.001); these outcomes occurred in 7 of 736 patients in the REGEN-COV 1200-mg group (1.0%) and in 24 of 748 patients in the placebo group who underwent randomization concurrently (3.2%) (relative risk reduction, 70.4%; P = 0.002). The median time to resolution of symptoms was 4 days shorter with each REGEN-COV dose than with placebo (10 days vs. 14 days; P<0.001 for both comparisons). REGEN-COV was efficacious across various subgroups, including patients who were SARS-CoV-2 serum antibody-positive at baseline. Both REGEN-COV doses reduced viral load faster than placebo; the least-squares mean difference in viral load from baseline through day 7 was -0.71 log
copies per milliliter (95% confidence interval CI, -0.90 to -0.53) in the 1200-mg group and -0.86 log
copies per milliliter (95% CI, -1.00 to -0.72) in the 2400-mg group. Serious adverse events occurred more frequently in the placebo group (4.0%) than in the 1200-mg group (1.1%) and the 2400-mg group (1.3%); infusion-related reactions of grade 2 or higher occurred in less than 0.3% of the patients in all groups.
REGEN-COV reduced the risk of Covid-19-related hospitalization or death from any cause, and it resolved symptoms and reduced the SARS-CoV-2 viral load more rapidly than placebo. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT04425629.).
Adaptive evolution is a key feature of T cell immunity. During acute immune responses, T cells harboring high-affinity T cell antigen receptors (TCRs) are preferentially expanded, but whether ...affinity maturation by clonal selection continues through the course of chronic infections remains unresolved. Here we investigated the evolution of the TCR repertoire and its affinity during the course of infection with cytomegalovirus, which elicits large T cell populations in humans and mice. Using single-cell and bulk TCR sequencing and structural affinity analyses of cytomegalovirus-specific T cells, and through the generation and in vivo monitoring of defined TCR repertoires, we found that the immunodominance of high-affinity T cell clones declined during the chronic infection phase, likely due to cellular senescence. These data showed that under conditions of chronic antigen exposure, low-affinity TCRs preferentially expanded within the TCR repertoire, with implications for immunotherapeutic strategies.
Critical thinking in E-learning environments Saadé, Raafat George; Morin, Danielle; Thomas, Jennifer D.E.
Computers in human behavior,
09/2012, Volume:
28, Issue:
5
Journal Article
Peer reviewed
► We investigated critical thinking in an online learning context (higher education). ► We examined the kinds of resources and activities that fosters/require critical thinking skills. ► Online ...interactive learning components are perceived to foster critical thinking. ► Design factors of interactive learning environments need to be addressed in online courses. ► Designers and teachers need to integrate more interactive components into the course activities.
One of the primary aims of higher education in today’s information technology enabled classroom is to make students more active in the learning process. The intended outcome of this increased IT-facilitated student engagement is to foster important skills such as critical thinking used in both academia and workplace environments. Critical thinking (CT) skills entails the ability(ies) of mental processes of discernment, analysis and evaluation to achieve a logical understanding. Critical thinking in the classroom as well as in the workplace is a central theme; however, with the dramatic increase of IT usage the mechanisms by which critical thinking is fostered and used has changed. This article presents the work and results of critical thinking in a virtual learning environment. We therefore present a web-based course and we assess in which parts of the course, and to what extent, critical thinking was perceived to occur. The course contained two categories of learning modules namely resources and interactive components. Critical thinking was measured subjectively using the ART scale. Results indicate the significance of “interactivity” in what students perceived to be critical-thinking-oriented versus online material as a resource. Results and opportunities that virtual environments present to foster critical thinking are discussed.
Abstract Magnetic nanoparticles (MNPs) have shown great promise for use as tools in a wide variety of biomedical applications, some of which require the delivery of large numbers of MNPs onto or into ...the cells of interest. Here we develop a quantifiable model cell system and show that intracellular delivery of even moderate levels of iron oxide (Fe2 O3 ) nanoparticles may adversely affect cell function. More specifically, we show that exposure to increasing concentrations of anionic MNPs, from 0.15 to 15 m m of iron, results in a dose-dependent diminishing viability and capacity of PC12 cells to extend neurites in response to their putative biological cue, i.e. nerve growth factor. The cytotoxicity results of biomaterials in our model system imply that more study into the acute and long-term effects of cellular Fe2 O3 internalization is both warranted and necessary.
Recent data suggest that complications and death from coronavirus disease 2019 (Covid-19) may be related to high viral loads.
In this ongoing, double-blind, phase 1-3 trial involving nonhospitalized ...patients with Covid-19, we investigated two fully human, neutralizing monoclonal antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, used in a combined cocktail (REGN-COV2) to reduce the risk of the emergence of treatment-resistant mutant virus. Patients were randomly assigned (1:1:1) to receive placebo, 2.4 g of REGN-COV2, or 8.0 g of REGN-COV2 and were prospectively characterized at baseline for endogenous immune response against SARS-CoV-2 (serum antibody-positive or serum antibody-negative). Key end points included the time-weighted average change in viral load from baseline (day 1) through day 7 and the percentage of patients with at least one Covid-19-related medically attended visit through day 29. Safety was assessed in all patients.
Data from 275 patients are reported. The least-squares mean difference (combined REGN-COV2 dose groups vs. placebo group) in the time-weighted average change in viral load from day 1 through day 7 was -0.56 log
copies per milliliter (95% confidence interval CI, -1.02 to -0.11) among patients who were serum antibody-negative at baseline and -0.41 log
copies per milliliter (95% CI, -0.71 to -0.10) in the overall trial population. In the overall trial population, 6% of the patients in the placebo group and 3% of the patients in the combined REGN-COV2 dose groups reported at least one medically attended visit; among patients who were serum antibody-negative at baseline, the corresponding percentages were 15% and 6% (difference, -9 percentage points; 95% CI, -29 to 11). The percentages of patients with hypersensitivity reactions, infusion-related reactions, and other adverse events were similar in the combined REGN-COV2 dose groups and the placebo group.
In this interim analysis, the REGN-COV2 antibody cocktail reduced viral load, with a greater effect in patients whose immune response had not yet been initiated or who had a high viral load at baseline. Safety outcomes were similar in the combined REGN-COV2 dose groups and the placebo group. (Funded by Regeneron Pharmaceuticals and the Biomedical and Advanced Research and Development Authority of the Department of Health and Human Services; ClinicalTrials.gov number, NCT04425629.).
Skeletal muscle aging results in a gradual loss of skeletal muscle mass, skeletal muscle function and regenerative capacity, which can lead to sarcopenia and increased mortality. Although the ...mechanisms underlying sarcopenia remain unclear, the skeletal muscle stem cell, or satellite cell, is required for muscle regeneration. Therefore, identification of signaling pathways affecting satellite cell function during aging may provide insights into therapeutic targets for combating sarcopenia. Here, we show that a cell-autonomous loss in self-renewal occurs via alterations in fibroblast growth factor receptor-1, p38α and p38β mitogen-activated protein kinase signaling in satellite cells from aged mice. We further demonstrate that pharmacological manipulation of these pathways can ameliorate age-associated self-renewal defects. Thus, our data highlight an age-associated deregulation of a satellite cell homeostatic network and reveal potential therapeutic opportunities for the treatment of progressive muscle wasting.
Monoclonal antibodies against SARS-CoV-2 are a clinically validated therapeutic option against COVID-19. Because rapidly emerging virus mutants are becoming the next major concern in the fight ...against the global pandemic, it is imperative that these therapeutic treatments provide coverage against circulating variants and do not contribute to development of treatment-induced emergent resistance. To this end, we investigated the sequence diversity of the spike protein and monitored emergence of virus variants in SARS-COV-2 isolates found in COVID-19 patients treated with the two-antibody combination REGEN-COV, as well as in preclinical in vitro studies using single, dual, or triple antibody combinations, and in hamster in vivo studies using REGEN-COV or single monoclonal antibody treatments. Our study demonstrates that the combination of non-competing antibodies in REGEN-COV provides protection against all current SARS-CoV-2 variants of concern/interest and also protects against emergence of new variants and their potential seeding into the population in a clinical setting.
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•REGEN-COV retains neutralization potency against current variants of concern/interest•In vitro escape studies can predict emergence of viral variants in animals and humans•3 noncompeting mAb in combination reduce variant risk compared to a combination of 2•Treatment with REGEN-COV in humans does not lead to emergence of viral variants
Treatment with monoclonal antibody combinations limits generation of SARS-CoV-2 escape variants in humans and model animals and protects against current variants of concern.
The coronavirus disease 2019 (COVID-19) pandemic could disproportionately affect individuals who have a substance use disorder (SUD). However, little information exists on COVID-19-related ...experiences among individuals with a SUD. We examined whether individuals with a SUD differ from other individuals with regard to COVID-19 testing, susceptibility, and employment-related vulnerability. We used data from a U.S. nationally representative survey (n = 1,208). Using logistic regressions, we examined whether individuals with SUDs differ from other individuals regarding underlying health conditions, COVID-19 testing, access to paid sick leave, and loss of employment. Data were collected in late May-early June, 2020. Four percent of participants reported that a healthcare professional had told them they had a SUD. We found that, compared to those without SUDs, respondents with SUDs had higher odds of having lost their job due to the pandemic (adjusted odds ratio AOR:5.17, 95% confidence interval CI:2.28-11.74). Among individuals who were employed prior to the pandemic, people with SUDs had lower odds of having paid sick leave (AOR:0.26, 95% CI:0.09-0.74). Our study indicates that individuals with SUDs could be disproportionately affected by COVID-19 economically, which might worsen SUD and racial/ethnic health disparities.
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