IGF1R is a potential new therapeutic target for HGNET-BCOR brain tumor patients

(1) Background: The high-grade neuroepithelial tumor of the central nervous system with BCOR alteration (HGNET-BCOR) is a highly malignant tumor. Preclinical models and molecular targets are urgently required for this cancer. Previous data suggest a potential role of insulin-like growth factor (IGF) signaling in HGNET-BCOR. (2) Methods: The primary HGNET-BCOR cells PhKh1 were characterized by western blot, copy number variation, and methylation analysis and by electron microscopy. The expression of IGF2 and IGF1R was assessed by qRT-PCR. The effect of chemotherapeutics and IGF1R inhibitors on PhKh1 proliferation was tested. The phosphorylation of IGF1R and downstream molecules was assessed by western blot. (3) Results: Phkh1 cells showed a DNA methylation profile compatible with the DNA methylation class “HGNET-BCOR” and morphologic features of cellular cannibalism. IGF2 and IGF1R were highly expressed by three HGNET-BCOR tumor samples and PhKh1 cells. PhKh1 cells were particularly sensitive to vincristine, vinblastine, actinomycin D (IC50 < 10 nM for all drugs), and ceritinib (IC50 = 310 nM). Ceritinib was able to abrogate the proliferation of PhKh1 cells and blocked the phosphorylation of IGF1R and AKT. (4) Conclusion: IGF1R is as an attractive target for the development of new therapy protocols for HGNET-BCOR patients, which may include ceritinib and vinblastine

Prácticas del enfermero en el contexto de la atención básica: scoping review

Objective: to identify and categorize the practices performed by nurses working in Primary Health Care and Family Health Strategy Units in light of responsibilities established by the profession’s legal and programmatic frameworks and by the Brazilian Unified Health System. Method: a scoping review was conducted in the following databases: LILACS, IBECS, BDENF, CINAHL and MEDLINE, and the Cochrane and SciELO libraries. Original research papers written by nurses addressing nursing practices in the primary health care context were included. Results: the review comprised 30 studies published between 2005 and 2014. Three categories emerged from the analysis: practices in the service; practices in the community; and management and education practices. Conclusion: the challenges faced by nurses are complex, as care should be centered on the population’s health needs, which requires actions at other levels of clinical and health responsibility. Brazilian nursing has achieved important advancements since the implementation of policies intended to reorganize work. There is, however, a need to shift work processes from being focused on individual procedures to being focused on patients so that an enlarged clinic is the ethical-political imperative guiding the organization of services and professional intervention.Objetivo: identificar e categorizar as práticas exercidas pelos enfermeiros junto às Unidades Básicas e às Equipes de Saúde da Família, à luz das atribuições previstas pelos marcos legais e programáticos da profissão e do Sistema Único de Saúde. Método: realizou-se uma revisão da literatura com o método scoping review, nas bases LILACS, IBECS, BDENF, CINAHL e MEDLINE, e nas bibliotecas Cochrane e SciELO. Incluíram-se artigos de pesquisa original, produzidos com enfermeiros, sobre as práticas de enfermagem no contexto dos cuidados de saúde primários. Resultados: a revisão abrangeu trinta estudos publicados entre 2005 e 2014. Da análise, resultaram três categorias: práticas no serviço, práticas na comunidade e práticas de gestão e formação. Conclusão: os desafios dos enfermeiros são complexos, posto que o cuidado deve estar centrado nas necessidades de saúde da população, o que remete à ação para outros níveis de responsabilidade clínica e sanitária. A enfermagem brasileira mostra importantes avanços desde a implantação das políticas de reorganização do trabalho. Necessita, entretanto, avançar no que se refere ao deslocamento dos processos de trabalho, focados em procedimentos individuais, para um processo mais voltado aos usuários, onde a clínica ampliada seja o imperativo ético-político da organização dos serviços e da intervenção profissional.Objetivo: identificar y categorizar las prácticas ejercidas por los enfermeros en las Unidades Básicas y los Equipos de Salud de la Familia, desde el punto de vista de las atribuciones previstas por los marcos legales y programáticos de la profesión y del Sistema Único de la Salud. Método: se realizó una revisión de la literatura con el método scoping review, en las bases LILACS, IBECS, BDENF, CINAHL y MEDLINE, y en las bibliotecas Cochrane y SciELO. Se incluyeron artículos de investigación original, producidos con enfermeros, sobre las prácticas de enfermería en el contexto de los cuidados de salud primarios. Resultados: la revisión abarcó treinta estudios publicados entre 2005 y 2014. Del análisis, resultaron tres categorías: prácticas en el servicio; prácticas en la comunidad; y, prácticas de administración y formación. Conclusión: los desafíos de los enfermeros son complejos, ya que el cuidado debe estar centrado en las necesidades de salud de la población, lo que conduce a la acción para otros niveles de responsabilidad clínica y sanitaria. La enfermería brasileña muestra importantes avances a partir de la implantación de las políticas de reorganización del trabajo. Necesita, entre tanto, avanzar en lo que se refiere al desplazamiento de los procesos de trabajo, enfocados en procedimientos individuales, para un proceso más dirigido a los usuarios, en donde la clínica ampliada sea el imperativo ético político de la organización de los servicios y de la intervención profesional.info:eu-repo/semantics/publishedVersio

Ceritinib-induced regression of an insulin-like growth factor-driven neuroepithelial brain tumor

The insulin-like growth factor (IGF) pathway plays an important role in several brain tumor entities. However, the lack of inhibitors crossing the blood–brain barrier remains a significant obstacle for clinical translation. Here, we targeted the IGF pathway using ceritinib, an off-target inhibitor of the IGF1 receptor (IGF1R) and insulin receptor (INSR), in a pediatric patient with an unclassified brain tumor and a notch receptor 1 (NOTCH1) germline mutation. Pathway analysis of the tumor revealed activation of the sonic hedgehog (SHH), the wingless and integrated-1 (WNT), the IGF, and the Notch pathway. The proliferation of the patient tumor cells (225ZL) was inhibited by arsenic trioxide (ATO), which is an inhibitor of the SHH pathway, by linsitinib, which is an inhibitor of IGF1R and INSR, and by ceritinib. 225ZL expressed INSR but not IGF1R at the protein level, and ceritinib blocked the phosphorylation of INSR. Our first personalized treatment included ATO, but because of side effects, we switched to ceritinib. After 46 days, we achieved a concentration of 1.70 µM of ceritinib in the plasma, and after 58 days, MRI confirmed that there was a response to the treatment. Ceritinib accumulated in the tumor at a concentration of 2.72 µM. Our data suggest ceritinib as a promising drug for the treatment of IGF-driven brain tumors

Characteristics of the diffuse astrophysical electron and tau neutrino flux with six years of IceCube high energy cascade data

We report on the first measurement of the astrophysical neutrino flux using particle showers (cascades) in IceCube data from 2010 -- 2015. Assuming standard oscillations, the astrophysical neutrinos in this dedicated cascade sample are dominated ($\sim 90 \%$) by electron and tau flavors. The flux, observed in the sensitive energy range from $16\,\mathrm{TeV}$ to $2.6\,\mathrm{PeV}$, is consistent with a single power-law model as expected from Fermi-type acceleration of high energy particles at astrophysical sources. We find the flux spectral index to be $\gamma=2.53\pm0.07$ and a flux normalization for each neutrino flavor of $\phi_{astro} = 1.66^{+0.25}_{-0.27}$ at $E_{0} = 100\, \mathrm{TeV}$, in agreement with IceCube's complementary muon neutrino results and with all-neutrino flavor fit results. In the measured energy range we reject spectral indices $\gamma\leq2.28$ at $\ge3\sigma$ significance level. Due to high neutrino energy resolution and low atmospheric neutrino backgrounds, this analysis provides the most detailed characterization of the neutrino flux at energies below $\sim100\,{\rm{TeV}}$ compared to previous IceCube results. Results from fits assuming more complex neutrino flux models suggest a flux softening at high energies and a flux hardening at low energies (p-value $\ge 0.06$). The sizable and smooth flux measured below $\sim 100\,{\rm{TeV}}$ remains a puzzle. In order to not violate the isotropic diffuse gamma-ray background as measured by the Fermi-LAT, it suggests the existence of astrophysical neutrino sources characterized by dense environments which are opaque to gamma-rays.Comment: 4 figures, 4 tables, includes supplementary materia

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements