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Colony-stimulating factor 1 (CSF1) and interleukin 34 (IL34) signal the CSF1 receptor to regulate macrophage differentiation. Studies in IL34- or CSF1-deficient mice have revealed that IL34 function is limited to the central nervous system and skin during development. However, the roles of IL34 and CSF1 at homeostasis or in the context of inflammatory diseases or cancer in wild-type mice have not been clarified . By neutralizing CSF1 and/or IL34 in adult mice, we identified that they play important roles in macrophage differentiation, specifically in steady-state microglia, Langerhans cells, and kidney macrophages. In several inflammatory models, neutralization of both CSF1 and IL34 contributed to maximal disease protection. However, in a myeloid cell-rich tumor model, CSF1 but not IL34 was required for tumor-associated macrophage accumulation and immune homeostasis. Analysis of human inflammatory conditions reveals IL34 upregulation that may account for the protection requirement of IL34 blockade. Furthermore, evaluation of IL34 and CSF1 blockade treatment during infection reveals no substantial safety concerns. Thus, IL34 and CSF1 play non-redundant roles in macrophage differentiation, and therapeutic intervention targeting IL34 and/or CSF1 may provide an effective treatment in macrophage-driven immune-pathologies.

Research is well established regarding teacher perceptions toward the inclusion of students with disabilities in the regular classroom. However, there is little current research on the topic of rural secondary teachers’ perceptions of their efficacy in the inclusion classroom. As a result, rural secondary education leaders have a limited knowledge base about how to prepare teachers to successfully implement the inclusion model in the general classroom. The purpose of this study was to compare the differences in rural secondary special and regular education teachers’ perceptions of their efficacy in teaching students with disabilities in the regular classroom. Specifically, this research sought to identify the differences in perceptions of general and special education teachers in the areas of student engagement, instructional practices, and classroom management. A causal-comparative quantitative design was used to examine the differences between the two groups. Fifteen school districts participated in the research study. The sample consisted of 148 regular education and 32 special education teachers from rural, secondary schools in Tennessee, who completed the Teachers’ Sense of Efficacy Scale survey. An independent-sample t test was analyzed, indicating there was a significant difference in the efficacy of student engagement and instructional practices for regular and special education teachers; however, no significant difference was found between regular and special education teachers in efficacy in classroom management. Further examination using stepwise multiple regression analysis was completed to determine the extent to which teacher characteristics (gender, level of education, number of college courses in special education, years of teaching experience, and amount of hours in training/professional development in coteaching) predict efficacy in student engagement, instructional strategies, and classroom management. In this analysis, the amount of hours in training/professional development in coteaching was a predictor of efficacy in student engagement. Similarly, the number of years of experience and the number of hours of training/professional development in coteaching was a predictor of efficacy in instructional practices and efficacy in classroom management. Gender, level of education, and number of college courses in special education were not significant contributors to the regression models. Further implications of the results are discussed.

The present study was conducted in order to determine the impact of a management development program on organizational performance. Specifically, the study evaluated the influence of management relations on union grievance filing rates. Eighty-two managers and subordinates completed a questionnaire both before and after the training program. Managers were assessed on six core competencies. Logistic Regression analysis indicated that improvement in the ability to manage relationships, give employees recognition for a job well done, and communicate performance expectations were predictive of a decrease in the grievance filing rate. In addition, Pearson Correlations revealed a negative association between subordinates' rating of management skills and the managers' self-reports of skills on two competencies. That of the ability to manage relationships and the ability to manage oneself. The findings are discussed from the standpoint of the appropriate theoretical paradigm for this type of evaluation. Specifically, the purpose of this study was to clarify the relationships between management development and organizational performance, and to address some of the critical measurement issues involved in the design of evaluations.

Adoptive transfer of antigen-specific T cells represents a major advance in cancer immunotherapy, with robust clinical outcomes in some patients 1 . Both the number of transferred T cells and their differentiation state are critical determinants of effective responses 2 , 3 . T cells can be expanded with T cell receptor (TCR)-mediated stimulation and interleukin-2, but this can lead to differentiation into effector T cells 4 , 5 and lower therapeutic efficacy 6 , whereas maintenance of a more stem-cell-like state before adoptive transfer is beneficial 7 . Here we show that H9T, an engineered interleukin-2 partial agonist, promotes the expansion of CD8 +  T cells without driving terminal differentiation. H9T led to altered STAT5 signalling and mediated distinctive downstream transcriptional, epigenetic and metabolic programs. In addition, H9T treatment sustained the expression of T cell transcription factor 1 (TCF-1) and promoted mitochondrial fitness, thereby facilitating the maintenance of a stem-cell-like state. Moreover, TCR-transgenic and chimeric antigen receptor-modified CD8 + T cells that were expanded with H9T showed robust anti-tumour activity in vivo in mouse models of melanoma and acute lymphoblastic leukaemia. Thus, engineering cytokine variants with distinctive properties is a promising strategy for creating new molecules with translational potential. H9T, an engineered IL-2 partial agonist, promotes the expansion of T cells while maintaining a stem-cell-like state, leading to improved efficacy of adoptive cell therapy in mouse models of melanoma and acute lymphoblastic leukaemia.

Pancreatic ductal adenocarcinoma (PDAC) cells use glutamine (Gln) to support proliferation and redox balance. Early attempts to inhibit Gln metabolism using glutaminase inhibitors resulted in rapid metabolic reprogramming and therapeutic resistance. Here, we demonstrated that treating PDAC cells with a Gln antagonist, 6-diazo-5-oxo- l -norleucine (DON), led to a metabolic crisis in vitro. In addition, we observed a profound decrease in tumor growth in several in vivo models using sirpiglenastat (DRP-104), a pro-drug version of DON that was designed to circumvent DON-associated toxicity. We found that extracellular signal-regulated kinase (ERK) signaling is increased as a compensatory mechanism. Combinatorial treatment with DRP-104 and trametinib led to a significant increase in survival in a syngeneic model of PDAC. These proof-of-concept studies suggested that broadly targeting Gln metabolism could provide a therapeutic avenue for PDAC. The combination with an ERK signaling pathway inhibitor could further improve the therapeutic outcome.