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Previous research suggests that psychotherapists' readiness to treat traumatized patients varies according to patient and therapist characteristics, including the patient's refugee background. : This study aims to examine the relationship between psychotherapists' readiness to treat patients with symptoms of post-traumatic stress disorder and various patient and therapist characteristics, including refugee background and country of origin. : In our vignette study with a nationwide online survey in Germany (  = 871), we assessed the readiness of licensed psychotherapists (LPTs) and therapists in training (PiTs) to treat patients with PTSD. Vignettes described patients with PTSD who differed in gender, refugee background, and country of origin (Syria vs. Ukraine). Participants rated treatment readiness and expected treatment success based on the vignette they received. : Treatment readiness and expected success were significantly lower for refugee patients. There was no difference in treatment readiness between refugees from Syria and Ukraine, but therapists expected less therapeutic success for Syrian patients compared to Ukrainian patients. Gender did not influence the results. The study shows that refugee background and country of origin influence psychotherapists' readiness to treat PTSD and their expectations of treatment success. These findings highlight potential reasons for the undertreatment of refugees and suggest opportunities for intervention and training, such as informing therapists about effective treatments for refugee patients.

Oncolytic viruses (OVs) are selected or designed to eliminate malignancies by direct infection and lysis of cancer cells. In contrast to this concept of direct tumor lysis by viral infection, we observed that a significant portion of the in vivo tumor killing activity of two OVs, vesicular stomatitis virus (VSV) and vaccinia virus is caused by indirect killing of uninfected tumor cells. Shortly after administering the oncolytic virus we observed limited virus infection, coincident with a loss of blood flow to the interior of the tumor that correlated with induction of apoptosis in tumor cells. Transcript profiling of tumors showed that virus infection resulted in a dramatic transcriptional activation of pro-inflammatory genes including the neutrophil chemoattractants CXCL1 and CXCL5. Immunohistochemical examination of infected tumors revealed infiltration by neutrophils correlating with chemokine induction. Depletion of neutrophils in animals prior to VSV administration eliminated uninfected tumor cell apoptosis and permitted more extensive replication and spreading of the virus throughout the tumor. Taken all together, these results indicate that targeted recruitment of neutrophils to infected tumor beds enhances the killing of malignant cells. We propose that activation of inflammatory cells can be used for enhancing the effectiveness of oncolytic virus therapeutics, and that this approach should influence the planning of therapeutic doses.

Endothelial cells (ECs) are components of the hematopoietic microenvironment and regulate hematopoietic stem and progenitor cell (HSPC) homeostasis. Cytokine treatments that cause HSPC trafficking to peripheral blood are associated with an increase in dipeptidylpeptidase 4/CD26 (DPP4/CD26), an enzyme that truncates the neurotransmitter neuropeptide Y (NPY). Here, we show that enzymatically altered NPY signaling in ECs caused reduced VE-cadherin and CD31 expression along EC junctions, resulting in increased vascular permeability and HSPC egress. Moreover, selective NPY2 and NPY5 receptor antagonists restored vascular integrity and limited HSPC mobilization, demonstrating that the enzymatically controlled vascular gateway specifically opens by cleavage of NPY by CD26 signaling via NPY2 and NPY5 receptors. Mice lacking CD26 or NPY exhibited impaired HSPC trafficking that was restored by treatment with truncated NPY. Thus, our results point to ECs as gatekeepers of HSPC trafficking and identify a CD26-mediated NPY axis that has potential as a pharmacologic target to regulate hematopoietic trafficking in homeostatic and stress conditions.

Endothelial cells (ECs) are components of the hematopoietic microenvironment and regulate hematopoietic stem and progenitor cell (HSPC) homeostasis. Cytokine treatments that cause HSPC trafficking to peripheral blood are associated with an increase in dipeptidylpeptidase 4/CD26 (DPP4/CD26), an enzyme that truncates the neurotransmitter neuropeptide Y (NPY). Here, we show that enzymatically altered NPY signaling in ECs caused reduced VE-cadherin and CD31 expression along EC junctions, resulting in increased vascular permeability and HSPC egress. Moreover, selective NPY2 and NPY5 receptor antagonists restored vascular integrity and limited HSPC mobilization, demonstrating that the enzymatically controlled vascular gateway specifically opens by cleavage of NPY by CD26 signaling via NPY2 and NPY5 receptors. Mice lacking CD26 or NPY exhibited impaired HSPC trafficking that was restored by treatment with truncated NPY. Thus, our results point to ECs as gatekeepers of HSPC trafficking and identify a CD26-mediated NPY axis that has potential as a pharmacologic target to regulate hematopoietic trafficking in homeostatic and stress conditions.

Endogenous prostaglandin E 2 (PGE 2 ) is a potent regulator of haematopoietic stem cell (HSC) retention in the bone marrow; inhibition of endogenous PGE 2 signalling by non-steroidal anti-inflammatory drugs results in enhanced HSC and haematopoietic progenitor cell mobility via E-prostanoid 4 (EP4) receptor antagonism. PGE 2 regulates stem-cell retention in bone marrow The haematopoietic stem cell (HSC) microenvironment supports progenitor cells producing new circulating blood cells yet prevents the inappropriate exit of immature cells into the bloodstream. This study identifies endogenous prostaglandin E 2 (PGE 2 ) as a component in the maintenance of this delicate balance. Louis M. Pelus and colleagues show that inhibition of endogenous PGE 2 signalling by nonsteroidal anti-inflammatory drugs (NSAIDs) significantly increases the release of functional haematopoietic stem and progenitors from bone marrow into the peripheral blood, with additive effects when used in conjunction with granulocyte colony-stimulating factor. Tests in primates and human volunteers suggest a strategy that might be used therapeutically to enhance transplantation survival: administration of NSAIDs (aspirin, ibuprofen and meloxicam) enhances stem-cell mobilization, with faster haematologic recovery and enhanced long-term stem-cell repopulation of haematopoietic grafts. To maintain lifelong production of blood cells, haematopoietic stem cells (HSCs) are tightly regulated by inherent programs and extrinsic regulatory signals received from their microenvironmental niche. Long-term repopulating HSCs reside in several, perhaps overlapping, niches that produce regulatory molecules and signals necessary for homeostasis and for increased output after stress or injury 1 , 2 , 3 , 4 , 5 . Despite considerable advances in the specific cellular or molecular mechanisms governing HSC–niche interactions, little is known about the regulatory function in the intact mammalian haematopoietic niche. Recently, we and others described a positive regulatory role for prostaglandin E 2 (PGE 2 ) on HSC function ex vivo 6 , 7 . Here we show that inhibition of endogenous PGE 2 by non-steroidal anti-inflammatory drug (NSAID) treatment in mice results in modest HSC egress from the bone marrow. Surprisingly, this was independent of the SDF-1–CXCR4 axis implicated in stem-cell migration. Stem and progenitor cells were found to have differing mechanisms of egress, with HSC transit to the periphery dependent on niche attenuation and reduction in the retentive molecule osteopontin. Haematopoietic grafts mobilized with NSAIDs had superior repopulating ability and long-term engraftment. Treatment of non-human primates and healthy human volunteers confirmed NSAID-mediated egress in other species. PGE 2 receptor knockout mice demonstrated that progenitor expansion and stem/progenitor egress resulted from reduced E-prostanoid 4 (EP4) receptor signalling. These results not only uncover unique regulatory roles for EP4 signalling in HSC retention in the niche, but also define a rapidly translatable strategy to enhance transplantation therapeutically.

To maintain lifelong production of blood cells, haematopoietic stem cells (HSCs) are tightly regulated by inherent programs and extrinsic regulatory signals received from their microenvironmental niche. Long-term repopulating HSCs reside in several, perhaps overlapping, niches that produce regulatory molecules and signals necessary for homeostasis and for increased output after stress or injury. Despite considerable advances in the specific cellular or molecular mechanisms governing HSC-niche interactions, little is known about the regulatory function in the intact mammalian haematopoietic niche. Recently, we and others described a positive regulatory role for prostaglandin E2 (PGE2) on HSC function ex vivo. Here we show that inhibition of endogenous PGE2 by nonsteroidal anti-inflammatory drug (NSAID) treatment in mice results in modest HSC egress from the bone marrow. Surprisingly, this was independent of the SDF-1-CXCR4 axis implicated in stem-cell migration. Stem and progenitor cells were found to have differing mechanisms of egress, with HSC transit to the periphery dependent on niche attenuation and reduction in the retentive molecule osteopontin. Haematopoietic grafts mobilized with NSAIDs had superior repopulating ability and long-term engraftment. Treatment of non-human primates and healthy human volunteers confirmed NSAID-mediated egress in other species. PGE2 receptor knockout mice demonstrated that progenitor expansion and stem/progenitor egress resulted from reduced E-prostanoid 4 (EP4) receptor signalling. These results not only uncover unique regulatory roles for EP4 signalling in HSC retention in the niche, but also define a rapidly translatable strategy to enhance transplantation therapeutically. [PUBLICATION ABSTRACT]