Targeting tachykinin receptors in neuroblastoma

Neuroblastoma is the most common extracranial tumor in children. Despite aggressive multimodal treatment, high-risk neuroblastoma remains a clinical challenge with survival rates below 50%. Adding targeted drugs to first-line therapy regimens is a promising approach to improve survival in these patients. TACR1 activation by substance P has been reported to be mitogenic in cancer cell lines. Tachykinin receptor (TACR1) antagonists are approved for clinical use as an antiemetic remedy since 2003. Tachykinin receptor inhibition has recently been shown to effectively reduce growth of several tumor types. Here, we report that neuroblastoma cell lines express TACR1, and that targeting TACR1 activity significantly reduced cell viability and induced apoptosis in neuroblastoma cell lines. Gene expression profiling revealed that TACR1 inhibition repressed E2F2 and induced TP53 signaling. Treating mice harboring established neuroblastoma xenograft tumors with Aprepitant also significantly reduced tumor burden. Thus, we provide evidence that the targeted inhibition of tachykinin receptor signaling shows therapeutic efficacy in preclinical models for high-risk neuroblastoma

Neutron and proton spectra from the decay of Λ\Lambda hypernuclei

We have determined the spectra of neutrons and protons following the decay of $\Lambda$ hypernuclei through the one- and two-nucleon induced mechanisms. The momentum distributions of the primary nucleons are calculated and a Monte Carlo simulation is used to account for final state interactions. From the spectra we calculate the number of neutrons ($N_n$) and protons ($N_p$) per $\Lambda$ decay and show how the measurement of these quantities, particularly $N_p$, can lead to a determination of $\Gamma_n / \Gamma_p$, the ratio of neutron to proton induced $\Lambda$ decay. We also show that the consideration of the two-nucleon induced channel has a repercussion in the results, widening the band of allowed values of $\Gamma_n / \Gamma_p$ with respect to what is obtained neglecting this channel.Comment: 30 pages, 12 Postscript figures, uuencoded file, ReVTeX, epsf.st

Defining the landscape of circular RNAs in neuroblastoma unveils a global suppressive function of MYCN

Circular RNAs (circRNAs) are a regulatory RNA class. While cancer-driving functions have been identified for single circRNAs, how they modulate gene expression in cancer is not well understood. We investigate circRNA expression in the pediatric malignancy, neuroblastoma, through deep whole-transcriptome sequencing in 104 primary neuroblastomas covering all risk groups. We demonstrate that MYCN amplification, which defines a subset of high-risk cases, causes globally suppressed circRNA biogenesis directly dependent on the DHX9 RNA helicase. We detect similar mechanisms in shaping circRNA expression in the pediatric cancer medulloblastoma implying a general MYCN effect. Comparisons to other cancers identify 25 circRNAs that are specifically upregulated in neuroblastoma, including circARID1A. Transcribed from the ARID1A tumor suppressor gene, circARID1A promotes cell growth and survival, mediated by direct interaction with the KHSRP RNA-binding protein. Our study highlights the importance of MYCN regulating circRNAs in cancer and identifies molecular mechanisms, which explain their contribution to neuroblastoma pathogenesis

Life design and career counseling: contributions to social justice

The chapter begins with the presentation of LDC framework. In the second section, considerations are given on LDC possibilities for enhancing decent work and social justice. From this perspective of social exclusion, designated social integrationist, participation in paid work is viewed as the key to social inclusion (Watts, 2001). At the end of this section the relevance of contextual factors in career development of disadvantaged populations is referred to highlight the importance of these interventions not be exclusively focused on inter- and intrapersonal career development factors, but also take into consideration social action at the institutional, community, public policy and international/global levels (Cook, 2017). In the next section, the process of balancing the focus on the self-determination of the individual with a focus on a transformation of contextual factors that reinforce the disadvantaged position (Blustein, et al., 2005; Prilleltensky, 1997) is illustrated by presenting an intervention in which LDC was integrated into supported employment approach. Our proposal focuses exclusively on collaborative activities at the individual, institutional and communal level, with these being the tiers which the counselor can more easily influence as part of their more routine interaction with disadvantaged populations in general. The chapter concludes with an overview of the subject and a reference on LDC limitations for the intervention with disadvantaged populations in general

Two and three nucleon induced photon absorption

We have investigated the mechanisms leading to two and three body photon absorption in nuclei. At photon energies around the pion production threshold we obtain a fraction of three body absorption of less than 10% of the total, contradicting previous theoretical claims that it dominates the absorption process. The strength of the three body channel grows smoothly with the photon energy reaching a maximum of about 60% of the total direct absorption at energies of the photon around 400 MeV