PIM1 inhibition effectively enhances Plerixafor-induced HSC mobilization

The CXCL12/CXCR4 axis regulates the interaction of hematopoietic stem cells (HSCs) with the niche and interruption of this pathway mobilizes HSCs from the bone marrow. Therefore CXCR4 antagonists like plerixafor are clinically used to collect HSCs from patients who fail to mobilize HSCs in response to G-CSF. Nevertheless plerixafor mobilization fails in 30% of the patients and the collection window lasts only 4-6h. As the CXCR4 surface expression on HSCs is regulated by the serine/threonine kinase PIM1, we aimed to improve HSC mobilization by combining CXCR4 and PIM1 inhibition. We found that CXCR4 inhibition using plerixafor leads to a compensatory upregulation of CXCR4 surface expression on HSCs. This effect can be reverted by deficiency or inhibition of PIM1. Consequently, HSC mobilization using plerixafor is strongly enhanced in Pim1-deficient mice. Likewise, treatment of WT animals with plerixafor in combination with the pan-PIM-inhibitor LGB321 leads to increased HSC mobilization. Furthermore, Cxcl-12 expression as well as CXCR4 surface expression in CXCL12-abundant reticular (CAR) cells is dramatically decreased in Pim1- deficient mice, resulting in impaired retention of HSCs. Targeting PIM kinases in combination with CXCR4 inhibition could thus improve the collection of stem cells in patients at risk for poor mobilization

Effects of the Communities that Heal (CTH) intervention on perceived opioid-related community stigma in the HEALing Communities Study: results of a multi-site, community-level, cluster-randomized trialResearch in context

Summary: Background: Community stigma against people with opioid use disorder (OUD) and intervention stigma (e.g., toward naloxone) exacerbate the opioid overdose crisis. We examined the effects of the Communities that HEAL (CTH) intervention on perceived opioid-related community stigma by stakeholders in the HEALing Communities Study (HCS). Methods: We collected three surveys from community coalition members in 66 communities across four states participating in HCS. Communities were randomized into Intervention (Wave 1) or Wait-list Control (Wave 2) arms. We conducted multilevel linear mixed models to compare changes in primary outcomes of community stigma toward people treated for OUD, naloxone, and medication for opioid use disorder (MOUD) by arm from time 1 (before the start of the intervention) to time 3 (end of the intervention period in the Intervention arm). Findings: Intervention stakeholders reported a larger decrease in perceived community stigma toward people treated for OUD (adjusted mean change (AMC) −3.20 [95% C.I. −4.43, −1.98]) and toward MOUD (AMC −0.33 [95% C.I. −0.56, −0.09]) than stakeholders in Wait-list Control communities (AMC −0.18 [95% C.I. −1.38, 1.02], p = 0.0007 and AMC 0.11 [95% C.I. −0.09, 0.31], p = 0.0066). The relationship between intervention status and change in stigma toward MOUD was moderated by rural-urban status (urban AMC −0.59 [95% CI, −0.87, −0.32], rural AMC not sig.) and state. The difference in stigma toward naloxone between Intervention and Wait-list Control stakeholders was not statistically significant (p = 0.18). Interpretation: The CTH intervention decreased stakeholder perceptions of community stigma toward people treated for OUD and stigma toward MOUD. Implementing the CTH intervention in other communities could decrease OUD stigma across diverse settings nationally. Funding: US National Institute on Drug Abuse