Ewing sarcoma (ES) is an aggressive malignancy driven by an oncogenic fusion protein, EWS-FLI1. Neuropeptide Y (NPY), and two of its receptors, Y1R and Y5R are up-regulated by EWS-FLI1 and abundantly expressed in ES cells. Paradoxically, NPY acting via Y1R and Y5R stimulates ES cell death. Here, we demonstrate that these growth-inhibitory actions of NPY are counteracted by hypoxia, which converts the peptide to a growth-promoting factor. In ES cells, hypoxia induces another NPY receptor, Y2R, and increases expression of dipeptidyl peptidase IV (DPPIV), an enzyme that cleaves NPY to a shorter form, NPY3-36. This truncated peptide no longer binds to Y1R and, therefore, does not stimulate ES cell death. Instead, NPY3-36 acts as a selective Y2R/Y5R agonist. The hypoxia-induced increase in DPPIV activity is most evident in a population of ES cells with high aldehyde dehydrogenase (ALDH) activity, rich in cancer stem cells (CSCs). Consequently, NPY, acting via Y2R/Y5Rs, preferentially stimulates proliferation and migration of hypoxic ALDHhigh cells. Hypoxia also enhances the angiogenic potential of ES by inducing Y2Rs in endothelial cells and increasing the release of its ligand, NPY3-36, from ES cells. In summary, hypoxia acts as a molecular switch shifting NPY activity away from Y1R/Y5R-mediated cell death and activating the Y2R/Y5R/DPPIV/NPY3-36 axis, which stimulates ES CSCs and promotes angiogenesis. Hypoxia-driven actions of the peptide such as these may contribute to ES progression. Due to the receptor-specific and multifaceted nature of NPY actions, these findings may inform novel therapeutic approaches to ES.

Neuroblastoma (NB) is a pediatric tumor of neural crest origin with heterogeneous phenotypes. While low stage tumors carry a favorable prognosis, over 50% of high risk NB relapses after treatment with a fatal outcome. Thus, developing therapies targeting refractory NB remains an unsolved clinical problem. Brain-derived neurotrophic factor (BDNF) and its TrkB receptor are known to protect NB cells from chemotherapy-induced cell death, while neuropeptide Y (NPY), acting via its Y2 receptor (Y2R), is an autocrine proliferative and angiogenic factor crucial for maintaining NB tumor growth. Here, we show that in NB cells, BDNF stimulates the synthesis of NPY and induces expression of another one of its receptors, Y5R. In human NB tissues, the expression of NPY and Y5R positively correlated with the expression of BDNF and TrkB. Functionally, BDNF triggered Y5R internalization in NB cells, while Y5R antagonist inhibited BDNF-induced p44/42-MAPK activation and its pro-survival activity. These observations suggested TrkB-Y5R transactivation that resulted in cross-talk between their signaling pathways. Additionally, NPY and Y5R were up-regulated in a BDNF-independent manner in NB cells under pro-apoptotic conditions, such as serum deprivation and chemotherapy, as well as in cell lines and tissues derived from post-treatment NB tumors. Blocking Y5R in chemoresistant NB cells rich in this receptor sensitized them to chemotherapy-induced apoptosis and inhibited their growth in vivo by augmenting cell death. In summary, the NPY/Y5R axis is an inducible survival pathway activated in NB by BDNF or cellular stress. Upon such activation, Y5R augments the pro-survival effect of BDNF via its interactions with TrkB receptor and exerts an additional BDNF-independent anti-apoptotic effect, both of which contribute to NB chemoresistance. Therefore, the NPY/Y5R pathway may become a novel therapeutic target for patients with refractory NB, thus far an incurable form of this disease.

Ewing sarcoma (ES) develops in bones or soft tissues of children and adolescents. The presence of bone metastases is one of the most adverse prognostic factors, yet the mechanisms governing their formation remain unclear. As a transcriptional target of EWS-FLI1, the fusion protein driving ES transformation, neuropeptide Y (NPY) is highly expressed and released from ES tumors. Hypoxia up-regulates NPY and activates its pro-metastatic functions. To test the impact of NPY on ES metastatic pattern, ES cell lines, SK-ES1 and TC71, with high and low peptide release, respectively, were used in an orthotopic xenograft model. ES cells were injected into gastrocnemius muscles of SCID/beige mice, the primary tumors excised, and mice monitored for the presence of metastases. SK-ES1 xenografts resulted in thoracic extra-osseous metastases (67%) and dissemination to bone (50%) and brain (25%), while TC71 tumors metastasized to the lungs (70%). Bone dissemination in SK-ES1 xenografts associated with increased NPY expression in bone metastases and its accumulation in bone invasion areas. The genetic silencing of NPY in SK-ES1 cells reduced bone degradation. Our study supports the role for NPY in ES bone invasion and provides new models for identifying pathways driving ES metastases to specific niches and testing anti-metastatic therapeutics.

SUMMARY The pattern of maturation of fine prehension in a group of 128 young children is described. This development culminates in the evolution of a dynamic tripod. The significance of this posture is discussed from a functional viewpoint and in relation to the assessment of children with neuromotor disorders. RÉSUMÉ La maturation de la préhension fine chez les jeunes en/ants Le pattern de maturation de la préhension fine dans un groupe de 128 enfants jeunes est étudié. Ce développement est à son apogée dans l'évolution d'un trépied dynamique. La signification de cette attitude posturale est discutée d'un point de vue fonctionnel et en relation avec l'examen d'enfants présentant des troubles neuromoteurs. ZUSAMMENFASSUNG Die Reifung des feinen Greifens bei jungen Kindern Der Reifungsvorgang des feinen Greifens ist in einer Gruppe von 128 jungen Kindern beschrieben. Diese Entwicklung kulminiert in der Ausbildung eines dynamischen Dreifußes. Die Bedeutung dieser Haltung wird von einem funktionellen Standpunkt und in Beziehung zu Ergebnissen bei Kindern mit neuromotorischen Erkrankungen diskutiert. RESUMEN La maduración de la prensión fina en el niño pequeño Se describe el esquema de la maduración de la prensión fina en un grupo de 128 niños pequeños. Este desarrollo culmina en un trípode dinámico. Se discute el significado de esta postura desde un punto de vista funcional y en relación con el reconocimiento de niños con alteraciones neuromotoras.

In light of the emphasis on enforcement-based approaches towards sex work, and the well-known negative impacts of these approaches on women's health, safety and well-being, we conducted a study to investigate the prevalence and correlates of recent incarceration among a cohort of women sex workers in Vancouver, Canada. Data were obtained from an open prospective community cohort of female and transgender women sex workers, known as An Evaluation of Sex Workers' Health Access (AESHA). Bivariate and multivariable logistic regression analyses, using generalized estimating equations (GEE), were used to model the effect of social and structural factors on the likelihood of incarceration over the 44-month follow-up period (January 2010-August 2013). Among 720 sex workers, 62.5 % (n = 450) reported being incarcerated in their lifetime and 23.9 % (n = 172) being incarcerated at least once during the study period. Of the 172 participants, about one third (36.6 %) reported multiple episodes of incarceration. In multivariable GEE analyses, younger age (adjusted odds ratio [AOR] = 1.04 per year younger, 95 % confidence interval [CI] 1.02-1.06), being of a sexual/gender minority (AOR = 1.62, 95 % CI 1.13-2.34), heavy drinking (AOR = 1.99, 95 % CI 1.20-3.29), being born in Canada (AOR = 3.28, 95 % CI 1.26-8.53), living in unstable housing conditions (AOR = 4.32, 95 % CI 2.17-8.62), servicing clients in public spaces (versus formal sex work establishments) (AOR = 2.33, 95 % CI 1.05-5.17) and experiencing police harassment without arrest (AOR = 1.82, 95 % CI 1.35-2.45) remain independently correlated with incarceration. This prospective study found a very high prevalence and frequency of incarceration among women sex workers in Vancouver, Canada, with the most vulnerable and marginalized women at increased risk of incarceration. Given the well-known social and health harms associated with incarceration, and associations between police harassment and incarceration in this study, our findings further add to growing calls to move away from criminalized and enforcement-based approaches to sex work in Canada and globally.