Binimetinib inhibits MEK and is effective against neuroblastoma tumor cells with low NF1 expression.

BackgroundNovel therapies are needed for children with high-risk and relapsed neuroblastoma. We hypothesized that MAPK/ERK kinase (MEK) inhibition with the novel MEK1/2 inhibitor binimetinib would be effective in neuroblastoma preclinical models.MethodsLevels of total and phosphorylated MEK and extracellular signal-regulated kinase (ERK) were examined in primary neuroblastoma tumor samples and in neuroblastoma cell lines by Western blot. A panel of established neuroblastoma tumor cell lines was treated with increasing concentrations of binimetinib, and their viability was determined using MTT assays. Western blot analyses were performed to examine changes in total and phosphorylated MEK and ERK and to measure apoptosis in neuroblastoma tumor cells after binimetinib treatment. NF1 protein levels in neuroblastoma cell lines were determined using Western blot assays. Gene expression of NF1 and MEK1 was examined in relationship to neuroblastoma patient outcomes.ResultsBoth primary neuroblastoma tumor samples and cell lines showed detectable levels of total and phosphorylated MEK and ERK. IC50 values for cells sensitive to binimetinib ranged from 8 nM to 1.16 μM, while resistant cells did not demonstrate any significant reduction in cell viability with doses exceeding 15 μM. Sensitive cells showed higher endogenous expression of phosphorylated MEK and ERK. Gene expression of NF1, but not MEK1, correlated with patient outcomes in neuroblastoma, and NF1 protein expression also correlated with responses to binimetinib.ConclusionsNeuroblastoma tumor cells show a range of sensitivities to the novel MEK inhibitor binimetinib. In response to binimetinib, sensitive cells demonstrated complete loss of phosphorylated ERK, while resistant cells demonstrated either incomplete loss of ERK phosphorylation or minimal effects on MEK phosphorylation, suggesting alternative mechanisms of resistance. NF1 protein expression correlated with responses to binimetinib, supporting the use of NF1 as a biomarker to identify patients that may respond to MEK inhibition. MEK inhibition therefore represents a potential new therapeutic strategy for neuroblastoma

Nifurtimox Is Effective Against Neural Tumor Cells and Is Synergistic with Buthionine Sulfoximine.

Children with aggressive neural tumors have poor survival rates and novel therapies are needed. Previous studies have identified nifurtimox and buthionine sulfoximine (BSO) as effective agents in children with neuroblastoma and medulloblastoma. We hypothesized that nifurtimox would be effective against other neural tumor cells and would be synergistic with BSO. We determined neural tumor cell viability before and after treatment with nifurtimox using MTT assays. Assays for DNA ladder formation and poly-ADP ribose polymerase (PARP) cleavage were performed to measure the induction of apoptosis after nifurtimox treatment. Inhibition of intracellular signaling was measured by Western blot analysis of treated and untreated cells. Tumor cells were then treated with combinations of nifurtimox and BSO and evaluated for viability using MTT assays. All neural tumor cell lines were sensitive to nifurtimox, and IC50 values ranged from approximately 20 to 210 μM. Nifurtimox treatment inhibited ERK phosphorylation and induced apoptosis in tumor cells. Furthermore, the combination of nifurtimox and BSO demonstrated significant synergistic efficacy in all tested cell lines. Additional preclinical and clinical studies of the combination of nifurtimox and BSO in patients with neural tumors are warranted

KorK

KorK setzt sich aus drei Wordteilen zusammen: „K“, „or“ (engl. oder) und „K“. Die zwei großen „K“ werden von zwei symmetrisch platzierten Schlagzeugern dargestellt, das „or“ wird vom Altsaxophon repräsentiert. Die drei Spieler bilden ein Dreieck im Raum. KorK bezieht sich auf besondere Weise auf den Klang des Materials Kork

I hear you with my eyes

für Klarinette, Posaune, Violoncello, Klavier, Schlagzeug und Live-Vide

Kreuz II

Thema des Stücks ist der allmähliche Übergang in den Klangfarben von Posaune (auf einer Tonhöhe gespielt) und der Trommel als Instrument mit (relativer) Tonhöh

Reconstruction of the Hirnantian (Late Ordovician) Palaeotopography in the Upper Yangtze Region

Reconstruction of the Hirnantian (Late Ordovician) palaeotopography in South China is important for understanding the distribution pattern of the Hirnantian marine depositional environment. In this study, we reconstructed the Hirnantian palaeotopography in the Upper Yangtze region based on the rankings of the palaeo-water depths, which were inferred according to the lithofacies and biofacies characteristics of the sections. Data from 374 Hirnantian sections were collected and standardized through the online Geobiodiversity Database. The Ordinary Kriging interpolation method in the ArcGIS software was applied to create the continuous surface of the palaeo-water depths, i.e. the Hirnantian palaeotopography. Meanwhile, the line transect analysis was used to further observe the terrain changes along two given directions. The reconstructed palaeotopographic map shows a relatively flat and shallow epicontinental sea with three local depressions and a submarine high on the Upper Yangtze region during the Hirnantian. The water depth is mostly less than 60 m and the Yangtze Sea gradually deepens towards the north

Biogeographic dynamics of graptolite species during the end-Ordovician mass extinction in South China

Spatial and temporal analysis of geographical biodiversity dynamics and reconstruction of species distribution areas are essential for revealing the patterns of evolution of graptolites and their survival strategies during bio-events. Over 800 occurrences of graptolites representing 84 species from five graptolite biozones (GB) through the interval of the end-Ordovician mass extinction (from the late Katian Dicellograptus complexus GB up to the early Rhuddanian Akidograptus ascensus GB) coming from 60 localities in South China were integrated for this study. All earlier identifications of taxa were updated following a unified taxonomic scheme and their distribution presented in a biozone-level stratigraphic correlation framework. The distribution areas of 26 species occurring in the study interval were reconstructed using GIS software whereby the convex hull areas and maximum distribution distances were calculated. Based on variations in geographical distribution and the relationship with the end-Ordovician mass extinction, graptolite species can be divided into three evolutionary types: the background extinction type, the mass extinction type, and the origination type. The first and second types belong to Diplograptina, and the third one belongs to Neograptina. The analysis of the reduction rate in the geographic distribution of diplograptid species shows that the extinction event not only hit the mass extinction type taxa, but also impacted those of the background extinction type. It also shows that the original distribution area of selected species is not directly related to their extinction risk. Changes in distribution areas of the graptolite species indicate the replacement of neograptids for diplograptids during the end-Ordovician mass extinction. To study patterns and changes in the spatial distribution of graptolite fauna, quantitative analyses of species-level α-, β-diversity, and occurrences were performed. Our results demonstrate that the end-Ordovician extinction mainly affected graptolites in the offshore and low-energy areas. Meanwhile, the extinction not only led to a sudden decline in the total diversity, but also resulted in a significant change in the composition and geographic differentiation of the graptolite fauna. Cluster analysis demonstrates that, before the extinction, the graptolite fauna showed two different geographic clusters, which resulted from the hydrodynamic conditions rather than from the distance to the coastline. After the extinction, the fauna became highly similar all over the study area, from nearshore to offshore and from high-energy to low-energy environments, which were mainly comprised by widespread, eurytopic species all over South China

Near-infrared quantum cutting in Ho3+, Yb3+-codoped BaGdF5 nanoparticles via first- and second-order energy transfers

Infrared quantum cutting involving Yb(3+) 950–1,000 nm ((2) F(5/2) → (2) F(7/2)) and Ho(3+) 1,007 nm ((5)S(2),(5)F(4) → (5)I(6)) as well as 1,180 nm ((5)I(6) → (5)I(8)) emissions is achieved in BaGdF(5): Ho(3+), Yb(3+) nanoparticles which are synthesized by a facile hydrothermal route. The mechanisms through first- and second-order energy transfers were analyzed by the dependence of Yb(3+) doping concentration on the visible and infrared emissions, decay lifetime curves of the (5) F(5) → (5)I(8), (5)S(2)/(5)F(4) → (5)I(8), and (5) F(3) → (5)I(8) of Ho(3+), in which a back energy transfer from Yb(3+) to Ho(3+) is first proposed to interpret the spectral characteristics. A modified calculation equation for quantum efficiency of Yb(3+)-Ho(3+) couple by exciting at 450 nm was presented according to the quantum cutting mechanism. Overall, the excellent luminescence properties of BaGdF(5): Ho(3+), Yb(3+) near-infrared quantum cutting nanoparticles could explore an interesting approach to maximize the performance of solar cells