The present study is a systematic review of school climate measures developed for a Spanish-speaking K-12 population. Four instruments were included in the analyses representing data of 9,236 students with a mean of sample size of 2,309 students. Evidences for test content and internal structure were the most frequent representation of psychometric validity. Internal consistency, represented by Cronbach’s alpha, ranged between 0.62 and 0.94. In addition, three instruments were translated from scales developed in the United States as evidence for test content validity. The findings of validity evidence, internal consistency, and context will guide school counselors in deciding the appropriate school climate measure to use among United States Latina/o students in Spanish. Consequently, the school climate assessment will compel school stakeholders to use results to advocate for the growth and inclusivity of Latina/o students.
Background: AXL receptor tyrosine kinase (AXL) is overexpressed in a variety of tumors and correlates with poor prognosis in cancer patients. AXL is expressed in cancer, stromal, and select immune cells, and has been implicated in the development of resistance to chemotherapy, targeted therapies & immunotherapies. Activation of AXL can be mediated by its ligand, growth arrest specific protein 6 (GAS6), or via ligand-independent homo/hetero-dimerization, both of which facilitate AXL phosphorylation, initiation of signaling cascades that promote cancer cell proliferation, survival, and an immunosuppressive microenvironment. Here we present the discovery and characterization of a novel, highly potent and selective AXL inhibitor, AB801. Materials and Methods: The potency and selectivity of AB801 against AXL and other kinases were determined using a panel of HTRF KinEASE-TK assays and via a competition binding assay utilizing DNA-tagged kinases. The effects of AB801 were further assessed by a cell-based phospho-AXL ELISA. The pharmacokinetic (PK) profile of the molecule was evaluated in preclinical species. AB801 was characterized in routine in vitro safety assays, including hERG inhibition. Downstream signaling of AXL was evaluated by phospho-array, Western blot, and qPCR. Pharmacodynamics (PD) and anti-tumor efficacy in combination with standard of care (SOC) therapies were assessed in murine cancer models. Results: The novel AXL inhibitor AB801 is potent, reversible, and selective. AB801 exhibits cellular activity at low nanomolar concentrations and retains significant activity in 100% human serum. Excellent selectivity was observed against MERTK (860x), TYRO3 (1,400x), and the overall kinome. Importantly, AB801 does not show significant CYP450 or hERG inhibition. Favorable preclinical PK is consistent with projected once-a-day oral administration in humans. AB801 increases sensitivity to SOC therapeutics such as chemotherapy, and results in increased DNA damage. Moreover, AB801 treatment sensitizes tumors to checkpoint blockade by increasing immune cell activation. Significant anti-tumor efficacy is observed in combination SOC therapies in multiple in vivo models. Conclusions: AXL inhibition is a promising therapeutic mechanism for impairing the growth of tumors resistant to SOC therapeutics. AB801 exhibits improved potency, selectivity, and safety profiles compared to other AXL inhibitors currently advancing into clinical development. Citation Format: Susan Lee Paprcka, Armon Goshayeshi, Suan Liu, Ruben Flores, Lauren Rocha, Jhansi L. Leslie, Dillon H. Miles, Corinne N. Foley, Shiwei Qu, Manjunath Lamani, Srinivas Paladugu, Hsin-Ting Huang, Nidhi Tribewal, Ada Chen, Joseph Kulusich, Stefan Garrido-Shaqfeh, Patricia Fabila, Salema Jafri, Anuja Devarajan, Ester Fernandez-Salas. AB801 is a highly potent and selective AXL kinase inhibitor that demonstrates significant anti-tumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 518.
Background: Immune suppression in the tumor microenvironment is known to contribute to tumor immune evasion. ILT2 (aka LILRB1) and ILT4 (aka LILRB2) are distinct ITIM-containing immunosuppressive receptors that recognize the shared ligand MHC-I. Both ILT2 and ILT4 are highly expressed on tumor infiltrating myeloid cells, while ILT2 is also expressed on tumor-associated T and NK cells. Given their common expression on myeloid cells, we anticipated that ILT2 and ILT4 blockade would be redundant. However, assays showed distinct functional activities of ILT2 or ILT4, with limited overlap. Here we explore the relative contribution of ILT2 and ILT4 on in vitro immune activation and in vivo anti-tumor activity. Methods: Anti-ILT2 and anti-ILT4 antibodies were assessed on T cells, NK cells and various myeloid cell subsets, including monocytes, macrophages, myeloid-derived suppressor cells (MDSC) and dendritic cells. ILT2 and ILT4 do not have clear murine orthologs; thus, to characterize in vivo activity, we utilized humanized murine tumor models, including PBMC-reconstituted and CD34-reconstituted mice. Mice were engrafted with tumors and treated with anti-ILT2, anti-ILT4, dual antagonist NGM707 and/or anti-PD-1 antagonist antibodies. Results: The in vitro and in vivo biology of ILT2 and ILT4 was explored using mono-specific antagonist antibodies, as well as the ILT2/ILT4 dual antagonist NGM707. Surprisingly, ILT2- and ILT4-specific antibodies showed distinct activities on myeloid cell populations, despite expression of both receptors. Using assays designed to induce optimal MHC-I engagement, both ILT2 and ILT4 contributed to myeloid suppression. ILT2 blockade further enhanced macrophage phagocytosis, CD8+ T cell cytolytic activity and activation of NKG2C+ memory-like NK cells. Humanized mouse models were used to characterize the in vivo anti-tumor activity of ILT2 and ILT4 blockade. Consistent with our in vitro findings, we observed a distinct effect of ILT2 and ILT4 blockade on tumor growth inhibition. Combination with an anti-PD-1 antibody further enhanced tumor suppression. Conclusions: Despite high expression of ILT2 and ILT4 on myeloid cell populations, evidence from standard in vitro assays suggested that ILT2 and ILT4 have distinct functional activities. Here, we provide evidence that both ILT2 and ILT4 play key roles in myeloid immune suppression, and that blockade of these two receptors can be additive or synergistic. ILT2 blockade additionally enhanced T cell and NK cell function. Furthermore, in vivo studies delineated a role for both ILT2 and ILT4 blockade in promoting anti-tumor immune responses and demonstrated that blockade of ILT2 and ILT4 is complementary to PD-1 inhibition. These data support the clinical evaluation of the dual ILT2/ILT4 antagonist antibody NGM707 alone and in combination with PD-1 blockade. Citation Format: Jane Tian, Samir Qurashi, Christina Song, Lauren Rocha, Kalyani Mondal, Suzanne Crawley, Sara Medfisch, Peirong Krisney Chen, Julie Roda, Jon Sitrin, Carmence Ho, Jonathan Aguayo, Lee Rivera, Jiawei Huang, Vicky Lin, David Shen, Yan Wang, Hui Tian, Alan Kutach, James Sissons, Daniel D. Kaplan, Geoffrey W. Stone. Immune inhibitory receptors ILT2 and ILT4 exhibit both distinct and overlapping biology in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 664.
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