Synergy between loss of NF1 and overexpression of MYCN in neuroblastoma is mediated by the GAP-related domain

Earlier reports showed that hyperplasia of sympathoadrenal cell precursors during embryogenesis in Nf1-deficient mice is independent of Nf1’s role in down-modulating RAS-MAPK signaling. We demonstrate in zebrafish that nf1 loss leads to aberrant activation of RAS signaling in MYCN-induced neuroblastomas that arise in these precursors, and that the GTPase-activating protein (GAP)-related domain (GRD) is sufficient to suppress the acceleration of neuroblastoma in nf1-deficient fish, but not the hypertrophy of sympathoadrenal cells in nf1 mutant embryos. Thus, even though neuroblastoma is a classical “developmental tumor”, NF1 relies on a very different mechanism to suppress malignant transformation than it does to modulate normal neural crest cell growth. We also show marked synergy in tumor cell killing between MEK inhibitors (trametinib) and retinoids (isotretinoin) in primary nf1a-/- zebrafish neuroblastomas. Thus, our model system has considerable translational potential for investigating new strategies to improve the treatment of very high-risk neuroblastomas with aberrant RAS-MAPK activation

Synergistic melanoma cell death mediated by inhibition of both MCL1 and BCL2 in high-risk tumors driven by NF1/PTEN loss

Melanomas driven by loss of the NF1 tumor suppressor have a high risk of treatment failure and effective therapies have not been developed. Here we show that loss-of-function mutations of nf1 and pten result in aggressive melanomas in zebrafish, representing the first animal model of NF1-mutant melanomas harboring PTEN loss. MEK or PI3K inhibitors show little activity when given alone due to cross-talk between the pathways, and high toxicity when given together. The mTOR inhibitors, sirolimus, everolimus, and temsirolimus, were the most active single agents tested, potently induced tumor-suppressive autophagy, but not apoptosis. Because addition of the BCL2 inhibitor venetoclax resulted in compensatory upregulation of MCL1, we established a three-drug combination composed of sirolimus, venetoclax, and the MCL1 inhibitor S63845. This well-tolerated drug combination potently and synergistically induces apoptosis in both zebrafish and human NF1/PTEN-deficient melanoma cells, providing preclinical evidence justifying an early-stage clinical trial in patients with NF1/PTEN-deficient melanoma

Hybrid suspension/solution precursor plasma spraying of a complex Ba(Mg1/3Ta2/3)O3 perovskite: Effects of processing parameters and precursor chemistry on phase formation and decomposition

Abstract: Ba(Mg1/3Ta2/3)O3 (BMT) has a high melting point and is envisioned as a thermal barrier coating material. In this study, a hybrid suspension/solution precursor plasma spray process with a radio frequency thermal plasma torch is designed to deposit BMT nanostructured coatings. Six combinations of chemical reagents are investigated as coating precursors: one BMT powder suspension and five Ta2O5 suspensions in nitrate- or acetate-based solutions. X-ray photoelectron spectroscopy is used to evaluate the element evaporation during plasma spraying, while a thermogravimetric/differential thermal analysis is applied to investigate the BMT formation. Parameters such as precursor chemistry, plasma power, spraying distance and substrate preheating are studied with regard to the coating phase structure. Twice the Mg stoichiometric amount with a power of 50 kW shows the best results when using nanocrystallized Ta2O5 as a tantalum precursor. When choosing nitrates as Ba and Mg precursors, crystallized BMT is obtained at lower plasma power (45 kW) when compared to acetates (50 kW). BaTa2O6, Ba3Ta5O15, Ba4Ta2O9, Mg4Ta2O9 are the main secondary phases observed during the BMT coatings deposition. Because of the complicated acetate decomposition process, the coating deposition rate from nitrate precursors is 1.56 times higher than that from acetate precursors

Coe Genes Are Expressed in Differentiating Neurons in the Central Nervous System of Protostomes

Genes of the coe (collier/olfactory/early B-cell factor) family encode Helix-Loop-Helix transcription factors that are widely conserved in metazoans and involved in many developmental processes, neurogenesis in particular. Whereas their functions during vertebrate neural tube formation have been well documented, very little is known about their expression and role during central nervous system (CNS) development in protostomes. Here we characterized the CNS expression of coe genes in the insect Drosophila melanogaster and the polychaete annelid Platynereis dumerilii, which belong to different subgroups of protostomes and show strikingly different modes of development. In the Drosophila ventral nerve cord, we found that the Collier-expressing cells form a subpopulation of interneurons with diverse molecular identities and neurotransmitter phenotypes. We also demonstrate that collier is required for the proper differentiation of some interneurons belonging to the Eve-Lateral cluster. In Platynereis dumerilii, we cloned a single coe gene, Pdu-coe, and found that it is exclusively expressed in post mitotic neural cells. Using an original technique of in silico 3D registration, we show that Pdu-coe is co-expressed with many different neuronal markers and therefore that, like in Drosophila, its expression defines a heterogeneous population of neurons with diverse molecular identities. Our detailed characterization and comparison of coe gene expression in the CNS of two distantly-related protostomes suggest conserved roles of coe genes in neuronal differentiation in this clade. As similar roles have also been observed in vertebrates, this function was probably already established in the last common ancestor of all bilaterians

A synthesis of research on language of reading instruction for English language learners

This article reviews experimental studies comparing bilingual and English-only reading programs for English language learners. The review method is best-evidence synthesis, which uses a systematic literature search, quantification of outcomes as effect sizes, and extensive discussion of individual studies that meet inclusion standards. A total of 17 studies met the inclusion standards. Among 13 studies focusing on elementary reading for Spanish-dominant students, 9 favored bilingual approaches on English reading measures, and 4 found no differences, for a median effect size of +0.45. Weighted by sample size, an effect size of +0.33 was computed, which is significantly different from zero (p < .05). One of two studies of heritage languages (French and Choctaw) and two secondary studies favored bilingual approaches. The review concludes that although the number of high-quality studies is small, existing evidence favors bilingual approaches, especially paired bilingual strategies that teach reading in the native language and English at different times each day. However, further research using longitudinal, randomized designs is needed to determine how best to ensure reading success for all English language learners