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

Small-molecule dual PLK1 and BRD4 inhibitors are active against preclinical models of pediatric solid tumors

Simultaneous inhibition of multiple molecular targets is an established strategy to improve the continuance of clinical response to therapy. Here, we screened 49 molecules with dual nanomolar inhibitory activity against BRD4 and PLK1, best classified as dual kinase-bromodomain inhibitors, in pediatric tumor cell lines for their antitumor activity. We identified two candidate dual kinase-bromodomain inhibitors with strong and tumor-specific activity against neuroblastoma, medulloblastoma, and rhabdomyosarcoma tumor cells. Dual PLK1 and BRD4 inhibitor treatment suppressed proliferation and induced apoptosis in pediatric tumor cell lines at low nanomolar concentrations. This was associated with reduced MYCN-driven gene expression as assessed by RNA sequencing. Treatment of patient-derived xenografts with dual inhibitor UMB103 led to significant tumor regression. We demonstrate that concurrent inhibition of two central regulators of MYC protein family of protooncogenes, BRD4, and PLK1, with single small molecules has strong and specific antitumor effects in preclinical pediatric cancer models

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

Mutational topography reflects clinical neuroblastoma heterogeneity

Neuroblastoma is a pediatric solid tumor characterized by strong clinical heterogeneity. Although clinical risk-defining genomic alterations exist in neuroblastomas, the mutational processes involved in their generation remain largely unclear. By examining the topography and mutational signatures derived from all variant classes, we identified co-occurring mutational footprints, which we termed mutational scenarios. We demonstrate that clinical neuroblastoma heterogeneity is associated with differences in the mutational processes driving these scenarios, linking risk-defining pathognomonic variants to distinct molecular processes. Whereas high-risk MYCN-amplified neuroblastomas were characterized by signs of replication slippage and stress, homologous recombination-associated signatures defined high-risk non-MYCN-amplified patients. Non-high-risk neuroblastomas were marked by footprints of chromosome mis-segregation and TOP1 mutational activity. Furthermore, analysis of subclonal mutations uncovered differential activity of these processes through neuroblastoma evolution. Thus, clinical heterogeneity of neuroblastoma patients can be linked to differences in the mutational processes that are active in their tumors

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