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To better understand the signaling complexity of AXL, a member of the tumor-associated macrophage (TAM) receptor tyrosine kinase family, we created a physical and functional map of AXL signaling interactions, phosphorylation events, and target-engagement of three AXL tyrosine kinase inhibitors (TKI). We assessed AXL protein complexes using proximity-dependent biotinylation (BioID), effects of AXL TKI on global phosphoproteins using mass spectrometry, and target engagement of AXL TKI using activity-based protein profiling. BioID identifies AXL-interacting proteins that are mostly involved in cell adhesion/migration. Global phosphoproteomics show that AXL inhibition decreases phosphorylation of peptides involved in phosphatidylinositol-mediated signaling and cell adhesion/migration. Comparison of three AXL inhibitors reveals that TKI RXDX-106 inhibits pAXL, pAKT, and migration/invasion of these cells without reducing their viability, while bemcentinib exerts AXL-independent phenotypic effects on viability. Proteomic characterization of these TKIs demonstrates that they inhibit diverse targets in addition to AXL, with bemcentinib having the most off-targets. AXL and EGFR TKI cotreatment did not reverse resistance in cell line models of erlotinib resistance. However, a unique vulnerability was identified in one resistant clone, wherein combination of bemcentinib and erlotinib inhibited cell viability and signaling. We also show that AXL is overexpressed in approximately 30% to 40% of nonsmall but rarely in small cell lung cancer. Cell lines have a wide range of AXL expression, with basal activation detected rarely. Our study defines mechanisms of action of AXL in lung cancers which can be used to establish assays to measure drug targetable active AXL complexes in patient tissues and inform the strategy for targeting it's signaling as an anticancer therapy.

Objectives: To better understand what knowledge translation activities are effective and meaningful to Indigenous communities and what is required to advance knowledge translation in health research with, for, and by Indigenous communities. Study design: Workshop and collaborative yarning. Setting: Lowitja Institute International Indigenous Health Conference, Cairns, June 2023. Participants: About 70 conference delegates, predominantly Indigenous people involved in research and Indigenous health researchers who shared their knowledge, experiences, and recommendations for knowledge translation through yarning and knowledge sharing. Results: Four key themes were developed using thematic analysis: knowledge translation is fundamental to research and upholding community rights; knowledge translation approaches must be relevant to local community needs and ways of mobilising knowledge; researchers and research institutions must be accountable for ensuring knowledge translation is embedded, respected and implemented in ways that address community priorities; and knowledge translation must be planned and evaluated in ways that reflect Indigenous community measures of success. Conclusion: Knowledge translation is fundamental to making research matter, and critical to ethical research. It must be embedded in all stages of research practice. Effective knowledge translation approaches are Indigenous‐led and move beyond Euro‐Western academic metrics. Institutions, funding bodies, and academics should embed structures required to uphold Indigenous knowledge translation. We join calls for reimaging health and medical research to embed Indigenous knowledge translation as a prerequisite for generative knowledge production that makes research matter. [ABSTRACT FROM AUTHOR]

Simple Summary: Cachexia occurs in up to 80% of patients with cancer. Although cancer-associated cachexia dramatically decreases overall survival and quality of life, it is often overlooked. To make meaningful progress in identifying cancer cachexia earlier and finding treatments for this condition, Moffitt Cancer Center held its first Cachexia Working Group Retreat in 2022. This manuscript describes the priorities discussed at the retreat and highlights collaborations that arose afterward. For many patients, the cancer continuum includes a syndrome known as cancer-associated cachexia (CAC), which encompasses the unintended loss of body weight and muscle mass, and is often associated with fat loss, decreased appetite, lower tolerance and poorer response to treatment, poor quality of life, and reduced survival. Unfortunately, there are no effective therapeutic interventions to completely reverse cancer cachexia and no FDA-approved pharmacologic agents; hence, new approaches are urgently needed. In May of 2022, researchers and clinicians from Moffitt Cancer Center held an inaugural retreat on CAC that aimed to review the state of the science, identify knowledge gaps and research priorities, and foster transdisciplinary collaborative research projects. This review summarizes research priorities that emerged from the retreat, examples of ongoing collaborations, and opportunities to move science forward. The highest priorities identified include the need to (1) evaluate patient-reported outcome (PRO) measures obtained in clinical practice and assess their use in improving CAC-related outcomes; (2) identify biomarkers (imaging, molecular, and/or behavioral) and novel analytic approaches to accurately predict the early onset of CAC and its progression; and (3) develop and test interventions (pharmacologic, nutritional, exercise-based, and through mathematical modeling) to prevent CAC progression and improve associated symptoms and outcomes. [ABSTRACT FROM AUTHOR]

Despite the global prioritization of addressing adolescent girls' and young women's sexual and reproductive health (SRH) and participatory rights, little research has examined their lived experiences in shaping their engagement in SRH decision-making processes in the global South. Further, few studies have explored how structural and societal factors influence their agency and participation. This critical and focused ethnography, informed by postcolonial feminist and difference-centred citizenship theories, conducted in Malawi (2017-2018) elicited perspectives of youth and key informants to help address these knowledge gaps. Our findings show that the effective implementation and uptake of global discourse on participation and gender equity is hindered by inadequate consideration of girls' and young women's local political, cultural and social realities. Many girls and young women demonstrate passion to participate in SRH policymaking as agents of change. However, patriarchal and gerontocratic political and social structures/institutions, and gendered and adultist norms and practices limit their active and meaningful participation in SRH decision-making. In addition, donors' roles in SRH policymaking and their prioritization of the "girl child" highlight an enduring postcolonial power over agenda-setting processes. Understanding young people's experiences of gendered participation and scrutinizing underlying systemic forces are critical steps toward realizing young women's SRH and participatory rights.

Background: Patients with adrenal insufficiency (AI) require life-long glucocorticoid (GC) replacement therapy. Within tissues, Cortisol (F) n availability is under the control of the isozymes of 11 β-hydroxysteroid dehydrogenase (11 β-HSD). We hypothesize that corticosteroid metabolism is altered in patients with AI because of the nonphysiological pattern of current immediate release hydrocortisone (IR-HC) replacement therapy. The use of a once-daily dual-release hydrocortisone (DR-HC) preparation, (Plenadren®), offers a more physiological cortisol profile and may alter corticosteroid metabolism in vivo. Study Design and Methods: Prospective crossover study assessing the impact of 12 weeks of DR-HC on systemic GC metabolism (urinary steroid metabolome profiling), cortisol activation in the liver (cortisone acetate challenge test), and subcutaneous adipose tissue (microdialysis, biopsy for gene expression analysis) in 51 patients with AI (primary and secondary) in comparison to IR-HC treatment and age- and BMI-matched controls. Results: Patients with AI receiving IR-HC had a higher median 24-hour urinary excretion of cortisol compared with healthy controls (72.1 Mg/24 hours [IQR 43.6-124.2] vs 51.9 µg/24 hours [35.5-72.3], P = .02), with lower global activity of 11β-HSD2 and higher 5-alpha reductase activity. b Following the switch from IR-HC to DR-HC therapy, there was a significant reduction in urinary cortisol and total GC metabolite excretion, which was most significant in the evening. There was an increase in 11 β-HSD2 activity. Hepatic 11 β-HSD1 activity was not significantly altered after switching to DR-HC, but there was a significant reduction in the expression and activity of 11 β-HSD1 in subcutaneous adipose tissue. Conclusion: Using comprehensive in vivo techniques, we have demonstrated abnormalities in corticosteroid metabolism in patients with primary and secondary AI receiving IR-HC. This dysregulation of pre-receptor glucocorticoid metabolism results in enhanced glucocorticoid activation in adipose tissue, which was ameliorated by treatment with DR-HC. [ABSTRACT FROM AUTHOR]