The Ethics of Care: Normative Structures and Empirical Implications

In this article I argue that the ethics of care provides us with a novel reading of human relations, and therefore makes possible a fresh approach to several empirical challenges. In order to explore this connection, I discuss some specific normative features of the ethics of care—primarily the comprehension of the moral agent and the concept of care—as these two key elements contribute substantially to a new ethical outlook. Subsequently, I argue that the relational and reciprocal mode of thinking with regard to the moral agent must be extended to our understanding of care. I term this comprehension “mature care”. Citing conflicts of interests as examples, I demonstrate how this conceptualization of care may further advance the ethics of care’s ability to take on empirical challenges. Finally, I discuss political implications that may emanate from the ethics of care and the concept of mature care

Epidermal Growth Factor-like 7 As a Novel Therapeutic Target in Mantle Cell Lymphoma

Abstract Mantle cell lymphoma (MCL) is an aggressive form of mature B-cell non-Hodgkin's lymphoma (NHL), accounting for nearly 6% of NHL cases. Currently, MCL patients are treated with aggressive chemo-immunotherapy regimens followed mostly by consolidation with autologous stem cell transplantation and maintenance rituximab. Despite these intensive therapies, MCL prognosis remains poor, with a median overall survival of 6-7 years, with most of the patients developing the refractory or recurrent disease. Thus, there is a need for novel and more effective, less toxic therapies for MCL. Epidermal growth factor-like 7 (EGFL7) is a protein secreted by endothelial cells and plays a critical role in angiogenesis. Our lab was the first to demonstrate a role for EGFL7 in hematologic malignancies, demonstrating that EGFL7 is increased in leukemic blasts of AML patients and that anti-EGFL7 treatment alone results in prolonged survival of leukemic mice (Papaioannou et al., 2017). While EGFL7 has been shown to play a role in some hematological malignancies, its role in MCL has not been investigated. Therefore, we assessed EGFL7 expression levels in MCL patients compared to healthy controls using the publicly available dataset GSE46846. We found significant increases in EGFL7 in malignant B cells from MCL patients compared to healthy individuals (p&amp;lt;0.05). Furthermore, using the publicly available clinical data set (Scott et al., 2017), we found that MCL patients (n=122) with high EGFL7 expression associated with lower overall survival rates compared to MCL patients with low EGFL7 (24 months; vs. 48 months, respectively, p= 0.0057) (Figure 1). To examine the therapeutic potential of targeting EGFL7 in MCL cells, we treated patient-derived xenograft (PDX) cells (n=3) with an anti-EGFL7 blocking antibody (Parsatuzumab) in vitro. We found an increase in apoptosis of MCL PDX cells compared to IgG control (15-50% vs. 0.5-2.4%, respectively), p&amp;lt;0.0001. Similar results were found when treating three MCL cell lines (Rec1, Jeko1, and SP53) with anti-EGFL7 or control. We found a decrease in cell proliferation (20 vs. 70%, p&amp;lt;0.0001) and an increase in apoptosis (67-87% vs. 8-17%, p&amp;lt;0.0001) at 48-hours post-anti-EGFL7 treatment compared to IgG, respectively. Next, to determine whether anti-EGFL7 treatment could target MCL cells in vivo, NSG mice were subcutaneously injected with Rec1 cells (5 x10 6). Seven days post-injection, mice were treated with anti-EGFL7 or IgG (50mg/kg, three times/week) (n=5 per group). Tumors were measured every week, and mice were sacrificed when they reached end point criteria. We found that anti-EGFL7 treated mice had significantly decreased tumor volume than IgG (1116.58mm 3 vs. 3626mm 3, respectively, p=0.0116) and increased survival (p = 0.0034). Overall, our data show that targeting EGFL7 using an anti-EGFL7 blocking antibody inhibits MCL cell growth and prolongs survival in mouse models of MCL. Our lab has previously shown that EGFL7 binds to the Epidermal growth factor receptor (EGFR) in AML (Bill et al., 2020). Knowing the importance of EGFR in lymphoma, we validated the binding of EGFL7 to EGFR in MCL cells by performing an immunoprecipitation (IP) assay on protein lysates from PDX cells (n=2) and Jeko1 cells. We found that EGFL7 protein was significantly enriched in protein fractions pulled down using anti-EGFR antibody compared to IgG. Conversely, we transfected Jeko1 cells with Flag-tagged EGFL7 plasmid and performed IP using anti-Flag antibody. EGFR protein was significantly enriched in the protein fraction pulled down using an anti-Flag antibody compared to IgG. Next, we examined the association between EGFL7 and EGFR expression in primary MCL patients and found that EGFR positively correlates with EGFL7 expression (n=122, r=0.1533). Further, Anti-EGFL7 treatment decreased phospho-AKT protein levels in PDX cells and MCL cell lines compared to IgG control, suggesting blocking EGFL7 abrogates EGFR mediated downstream signals. In conclusion, this is the first report describing a role for EGFL7 in MCL growth and/or survival by modulating the EGFR-AKT signaling pathway and targeting EGFL7 using an anti-EGFL7 blocking antibody as a novel treatment to improve the outcome for MCL patients. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare. </jats:sec

Modulating Endothelial Cells with EGFL7 to Diminish aGVHD after Allogeneic Bone Marrow Transplantation in Mice

Abstract Acute graft versus host (aGVHD) is the second cause of death after allogeneic-hematopoietic stem cell transplant (allo-HSCT) underscoring the need for novel therapies. Based on previous work that endothelial cell dysfunction is present in aGVHD and that epidermal growth factor-like domain 7 (EGFL7) plays a significant role in decreasing inflammation by repressing endothelial cell activation and T cell migration, we hypothesized that increasing EGFL7 levels after allo-HSCT will diminish the severity of aGVHD. Here, we show that treatment with recombinant EGFL7 (rEGFL7) decreases aGVHD severity and improves survival in recipient mice after allogeneic transplantation with respect to controls without affecting graft versus leukemia effect. Histopathology analysis revealed higher amount of leukocyte infiltration in both large intestine and liver of PBS group compared to rEGFL7-treated mice. Furthermore, damage to the gut was reduced in EGFL7 treated mice. Finally, we showed that rEGFL7 treatment results in higher thymocytes, T, B and dendritic cells in recipient mice after allo-HSCT. This study constitutes a proof of concept of the ability of rEGFL7 therapy to reduce GHVD severity and mortality after allo-HSCT. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare. </jats:sec

Walking and talking: an investigation of cognitive-motor dual tasking in multiple sclerosis

Background: Deficits in motor functioning, including walking, and in cognitive functions, including attention, are known to be prevalent in multiple sclerosis (MS), though little attention has been paid to how impairments in these areas of functioning interact. Objectives: This study investigated the effects of performing a concurrent cognitive task when walking in people with MS. Level of task demand was manipulated to investigate whether this affected level of dual-task decrement. Method: Eighteen participants with MS and 18 healthy controls took part. Participants completed walking and cognitive tasks under single- and dual-task conditions. Results: Compared to healthy controls, MS participants showed greater decrements in performance under dual-task conditions in cognitive task performance, walking speed and swing time variability. In the MS group, the degree of decrement under dual-task conditions was related to levels of fatigue, a measure of general cognitive functioning and self-reported everyday cognitive errors, but not to measures of disease severity or duration. Conclusions: Difficulty with walking and talking in MS may be a result of a divided attention deficit or of overloading of the working memory system, and further investigation is needed. We suggest that difficulty with walking and talking in MS may lead to practical problems in everyday life, including potentially increasing the risk of falls. Clinical tools to assess cognitive—motor dual-tasking ability are needed