Delineation of the frequency and boundary of chromosomal copy number variations in paediatric neuroblastoma

© 2018 Informa UK Limited, trading as Taylor & Francis Group. Neuroblastoma, the most common solid tumour in early childhood, is characterized by very frequent chromosomal copy number variations (CNVs). While chromosome 2p amplification, 17q gain, 1p and 11q deletion in human neuroblastoma tissues are well-known, the exact frequencies and boundaries of the chromosomal CNVs have not been delineated. We analysed the publicly available single nucleotide polymorphism (SNP) array data which were originally generated by the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative, defined the frequencies and boundaries of chromosomes 2p11.2–2p25.3 amplification, 17q11.1-17q25.3 gain, 1p13.3-1p36.33 deletion and 11q13.3-11q25 deletion in neuroblastoma tissues, and identified chromosome 7q14.1 (Chr7:38254795-38346971) and chromosome 14q11.2 (Chr14:21637401-22024617) deletion in blood and bone marrow samples from neuroblastoma patients, but not in tumour tissues. Kaplan Meier analysis showed that double deletion of Chr7q14.1 and Chr14q11.2 correlated with poor prognosis in MYCN gene amplified neuroblastoma patients. In conclusion, the oncogenes amplified or gained and tumour suppressor genes deleted within the boundaries of chromosomal CNVs in tumour tissues should be studied for their roles in tumourigenesis and as therapeutic targets. Focal deletions of Chr7q14.1 and Chr14q11.2 together in blood and bone marrow samples from neuroblastoma patients can be used as a marker for poorer prognosis and more aggressive therapies

Giant topological and planar Hall effect in Cr1/3NbS2

Cr1/3NbS2 is a transition metal dichalcogenide that has been of significant interest due to its ability to host a magnetic chiral soliton lattice. Conventional and planar Hall measurements provide valuable insight into the detection of exotic spin structures in chiral magnets. We show that the presence of a giant planar Hall effect (PHE) can be attributed to a tilted soliton lattice in Cr1/3NbS2. Our detailed angular-dependent study shows the PHE and anisotropic magnetoresistance are intrinsically linked in complex noncoplanar magnets. From the conventional Hall signal we show the presence of a giant unconventional, likely topological Hall component that is the fingerprint of noncoplanar spin textures

Dynamics of Nonequilibrium Dicke Models

Motivated by experiments observing self-organization of cold atoms in optical cavities we investigate the collective dynamics of the associated nonequilibrium Dicke model. The model displays a rich semiclassical phase diagram of long time attractors including distinct superradiant fixed points, bistable and multistable coexistence phases and regimes of persistent oscillations. We explore the intrinsic timescales for reaching these asymptotic states and discuss the implications for finite duration experiments. On the basis of a semiclassical analysis of the effective Dicke model we find that sweep measurements over 200ms may be required in order to access the asymptotic regime. We briefly comment on the corrections that may arise due to quantum fluctuations and states outside of the effective two-level Dicke model description.Comment: 27 pages, 20 figure

Anisotropic skyrmion and multi-qq spin dynamics in centrosymmetric Gd2_2PdSi3_3

Skyrmions are particle-like vortices of magnetization with non-trivial topology, which are usually stabilized by Dzyaloshinskii-Moriya interactions (DMI) in noncentrosymmetric bulk materials. Exceptions are centrosymmetric Gd- and Eu-based skyrmion-lattice (SkL) hosts with net-zero DMI, where both the SkL stabilization mechanisms and magnetic ground states remain controversial. We address these by investigating both static and dynamic spin properties of the centrosymmetric SkL host Gd$_2$PdSi$_3$ using muon spectroscopy ($\mu$SR). We find that spin fluctuations in its non-coplanar SkL phase are highly anisotropic, implying that spin anisotropy plays a prominent role in stabilizing this phase. We also observe strongly-anisotropic spin dynamics in the ground-state (IC-1) incommensurate magnetic phase of the material, indicating that it is a meron-like multi-$q$ structure. In contrast, the higher-field, coplanar IC-2 phase is found to be single-$q$ with nearly-isotropic spin dynamics.Comment: Main text: 7 pages, 3 figures. Supplemental Material: 6 pages, 5 figure

Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design.

Accelerating cures for children with cancer remains an immediate challenge as a result of extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs)-many of which are refractory to current standard-of-care treatments-from high-risk childhood cancers. Here, we genomically characterize 261 PDX models from 37 unique pediatric cancers; demonstrate faithful recapitulation of histologies and subtypes; and refine our understanding of relapsed disease. In addition, we use expression signatures to classify tumors for TP53 and NF1 pathway inactivation. We anticipate that these data will serve as a resource for pediatric oncology drug development and will guide rational clinical trial design for children with cancer

Diagnostic classification of childhood cancer using multiscale transcriptomics

The causes of pediatric cancers’ distinctiveness compared to adult-onset tumors of the same type are not completely clear and not fully explained by their genomes. In this study, we used an optimized multilevel RNA clustering approach to derive molecular definitions for most childhood cancers. Applying this method to 13,313 transcriptomes, we constructed a pediatric cancer atlas to explore age-associated changes. Tumor entities were sometimes unexpectedly grouped due to common lineages, drivers or stemness profiles. Some established entities were divided into subgroups that predicted outcome better than current diagnostic approaches. These definitions account for inter-tumoral and intra-tumoral heterogeneity and have the potential of enabling reproducible, quantifiable diagnostics. As a whole, childhood tumors had more transcriptional diversity than adult tumors, maintaining greater expression flexibility. To apply these insights, we designed an ensemble convolutional neural network classifier. We show that this tool was able to match or clarify the diagnosis for 85% of childhood tumors in a prospective cohort. If further validated, this framework could be extended to derive molecular definitions for all cancer types

Spin density waves and ground state helices in EuGa2.4Al1.6

The Eu⁢(Ga1−⁢Al)4 series is composed of centrosymmetric structures which exhibit a wide range of rich topological phenomena, including some members hosting magnetic skyrmions. In this letter, we investigate the previously unreported intermediate compound EuGa2.4⁢Al1.6, which hosts two distinct phase transitions under zero applied magnetic field. We have used resonant elastic x-ray scattering with full linear polarization analysis to unambiguously determine the zero-field magnetic structures, which consist of a transition between a basal plane transverse spin density wave at higher temperatures into a noncollinear helical ground state. Furthermore, we demonstrate a phase coexistence regime below the transition and reveal an elliptically modulated helical magnetic structure emerging from wavevector splitting

Double-Q ground state with topological charge stripes in the centrosymmetric skyrmion candidate GdRu2Si2

GdRu2Si2 is a centrosymmetric magnet in which a skyrmion lattice has recently been discovered. Here, we investigate the magnetic structure of the zero-field ground state using neutron diffraction on single crystal and polycrystalline 160GdRu2Si2. In addition to observing the principal propagation vectors q1 and q2, we discover higher-order magnetic satellites, notably q1 + 2q2. The appearance of these satellites is explained within the framework of a double-Q constant-moment solution. Using powder diffraction, we implement a quantitative refinement of this model. This structure, which contains vortexlike motifs, is shown to have a one-dimensional topological charge density

The long noncoding RNA lncNB1 promotes tumorigenesis by interacting with ribosomal protein RPL35

The majority of patients with neuroblastoma due to MYCN oncogene amplification and consequent N-Myc oncoprotein over-expression die of the disease. Here our analyses of RNA sequencing data identify the long noncoding RNA lncNB1 as one of the transcripts most over-expressed in MYCN-amplified, compared with MYCN-non-amplified, human neuroblastoma cells and also the most over-expressed in neuroblastoma compared with all other cancers. lncNB1 binds to the ribosomal protein RPL35 to enhance E2F1 protein synthesis, leading to DEPDC1B gene transcription. The GTPase-activating protein DEPDC1B induces ERK protein phosphorylation and N-Myc protein stabilization. Importantly, lncNB1 knockdown abolishes neuroblastoma cell clonogenic capacity in vitro and leads to neuroblastoma tumor regression in mice, while high levels of lncNB1 and RPL35 in human neuroblastoma tissues predict poor patient prognosis. This study therefore identifies lncNB1 and its binding protein RPL35 as key factors for promoting E2F1 protein synthesis, N-Myc protein stability and N-Myc-driven oncogenesis, and as therapeutic targets