Identification and pharmacological inactivation of the MYCN gene network as a therapeutic strategy for neuroblastic tumor cells

This research was originally published in Journal of Biological Chemistry. Olesya Chayka, Cosimo Walter D’Acunto, Odette Middleton, Maryam Arab, and Arturo Sala. Identification and Pharmacological Inactivation of the MYCN Gene Network as a Therapeutic Strategy for Neuroblastic Tumor Cells. Journal of Biological Chemistry. 2015; Vol 290 (4) :pp. 2198 - 2212. © the American Society for Biochemistry and Molecular Biology.This article has been made available through the Brunel Open Access Publishing Fund.The MYC family of transcription factors consists of three well characterized members, c-MYC, L-MYC, and MYCN, deregulated in the majority of human cancers. In neuronal tumors such as neuroblastoma, MYCN is frequently activated by gene amplification, and reducing its expression by RNA interference has been shown to promote growth arrest and apoptosis of tumor cells. From a clinical perspective, RNA interference is not yet a viable option, and small molecule inhibitors of transcription factors are difficult to develop. We therefore planned to identify, at the global level, the genes interacting functionally with MYCN required to promote fitness of tumor cells facing oncogenic stress. To find genes whose inactivation is synthetically lethal to MYCN, we implemented a genome-wide approach in which we carried out a drop-out shRNA screen using a whole genome library that was delivered into isogenic neuroblastoma cell lines expressing or not expressing MYCN. After the screen, we selected for in-depth analysis four shRNAs targeting AHCY, BLM, PKMYT1, and CKS1B. These genes were chosen because they are directly regulated by MYC proteins, associated with poor prognosis of neuroblastoma patients, and inhibited by small molecule compounds. Mechanistically, we found that BLM and PKMYT1 are required to limit oncogenic stress and promote stabilization of the MYCN protein. Cocktails of small molecule inhibitors of CKS1B, AHCY, BLM, and PKMYT1 profoundly affected the growth of all neuroblastoma cell lines but selectively caused death of MYCN-amplified cells. Our findings suggest that drugging the MYCN network is a promising avenue for the treatment of high risk, neuroblastic cancers.SPARKS and the Neuroblastoma Society

Using academic notebooks to support achievement and promote positive environments in differentiated classrooms

Authors Examine How the Use of Academic Notebooks Impacts Collaborative Learning Experiences of Young Adolescent

Collective Transport in Arrays of Quantum Dots

(WORDS: QUANTUM DOTS, COLLECTIVE TRANSPORT, PHYSICAL EXAMPLE OF KPZ) Collective charge transport is studied in one- and two-dimensional arrays of small normal-metal dots separated by tunnel barriers. At temperatures well below the charging energy of a dot, disorder leads to a threshold for conduction which grows linearly with the size of the array. For short-ranged interactions, one of the correlation length exponents near threshold is found from a novel argument based on interface growth. The dynamical exponent for the current above threshold is also predicted analytically, and the requirements for its experimental observation are described.Comment: 12 pages, 3 postscript files included, REVTEX v2, (also available by anonymous FTP from external.nj.nec.com, in directory /pub/alan/dotarrays [as separate files]) [replacement: FIX OF WRONG VERSION, BAD SHAR] March 17, 1993, NEC

Novel Identification of LYVE-1 Positive Macrophages in Rheumatoid Synovial Tissue

Objective: LYVE-1+ macrophages are observed in a range of cancers, where they play a role in tumour lymphangiogenesis. In rheumatoid arthritis (RA), lymphangiogenesis increases in the early stage of the disease and decreases as it progresses, potentially exacerbating inflammatory cell persistence. We investigated whether LYVE-1+ macrophages were present in RA synovium. Methods: Synovial tissue from RA patients was obtained at joint replacement surgery and immunohistochemistry was performed to visualise LYVE-1+ and CD68+ cells. Results: LYVE-1+ macrophages were present in rheumatoid synovial tissue, the first observation of this kind. Conclusion: Despite the reduction in lymphangiogenesis in chronic RA, LYVE-1 positive macrophages are present and there is a potential role for macrophages in the generation of lymphatic vessels

Bonding machine for forming a solar array strip

A machine is described for attaching solar cells to a flexable substrate on which printed circuitry has been deposited. The strip is fed through: (1) a station in which solar cells are elevated into engagement with solder pads for the printed circuitry and thereafter heated by an infrared lamp; (2) a station at which flux and solder residue is removed; (3) a station at which electrical performance of the soldered cells is determined; (4) a station at which an encapsulating resin is deposited on the cells; (5) a station at which the encapsulated solar cells are examined for electrical performance; and (6) a final station at which the resulting array is wound on a takeup drum

Increasing impacts of extreme droughts on vegetation productivity under climate change

Terrestrial gross primary production (GPP) is the basis of vegetation growth and food production globally1 and plays a critical role in regulating atmospheric CO2 through its impact on ecosystem carbon balance. Even though higher CO2 concentrations in future decades can increase GPP2, low soil water availability, heat stress and disturbances associated with droughts could reduce the benefits of such CO2 fertilization. Here we analysed outputs of 13 Earth system models to show an increasingly stronger impact on GPP by extreme droughts than by mild and moderate droughts over the twenty-first century. Due to a dramatic increase in the frequency of extreme droughts, the magnitude of globally averaged reductions in GPP associated with extreme droughts was projected to be nearly tripled by the last quarter of this century (2075–2099) relative to that of the historical period (1850–1999) under both high and intermediate GHG emission scenarios. By contrast, the magnitude of GPP reductions associated with mild and moderate droughts was not projected to increase substantially. Our analysis indicates a high risk of extreme droughts to the global carbon cycle with atmospheric warming; however, this risk can be potentially mitigated by positive anomalies of GPP associated with favourable environmental conditions

A middleware for a large array of cameras

Large arrays of cameras are increasingly being employed for producing high quality image sequences needed for motion analysis research. This leads to the logistical problem with coordination and control of a large number of cameras. In this paper, we used a lightweight multi-agent system for coordinating such camera arrays. The agent framework provides more than a remote sensor access API. It allows reconfigurable and transparent access to cameras, as well as software agents capable of intelligent processing. Furthermore, it eases maintenance by encouraging code reuse. Additionally, our agent system includes an automatic discovery mechanism at startup, and multiple language bindings. Performance tests showed the lightweight nature of the framework while validating its correctness and scalability. Two different camera agents were implemented to provide access to a large array of distributed cameras. Correct operation of these camera agents was confirmed via several image processing agents

Spin and link overlaps in 3-dimensional spin glasses

Excitations of three-dimensional spin glasses are computed numerically. We find that one can flip a finite fraction of an LxLxL lattice with an O(1) energy cost, confirming the mean field picture of a non-trivial spin overlap distribution P(q). These low energy excitations are not domain-wall-like, rather they are topologically non-trivial and they reach out to the boundaries of the lattice. Their surface to volume ratios decrease as L increases and may asymptotically go to zero. If so, link and window overlaps between the ground state and these excited states become ``trivial''.Comment: Extra fits comparing TNT to mean field, summarized in a tabl

On the driven Frenkel-Kontorova model: II. Chaotic sliding and nonequilibrium melting and freezing

The dynamical behavior of a weakly damped harmonic chain in a spatially periodic potential (Frenkel-Kontorova model) under the subject of an external force is investigated. We show that the chain can be in a spatio-temporally chaotic state called fluid-sliding state. This is proven by calculating correlation functions and Lyapunov spectra. An effective temperature is attributed to the fluid-sliding state. Even though the velocity fluctuations are Gaussian distributed, the fluid-sliding state is clearly not in equilibrium because the equipartition theorem is violated. We also study the transition between frozen states (stationary solutions) and=7F molten states (fluid-sliding states). The transition is similar to a first-order phase transition, and it shows hysteresis. The depinning-pinning transition (freezing) is a nucleation process. The frozen state contains usually two domains of different particle densities. The pinning-depinning transition (melting) is caused by saddle-node bifurcations of the stationary states. It depends on the history. Melting is accompanied by precursors, called micro-slips, which reconfigurate the chain locally. Even though we investigate the dynamics at zero temperature, the behavior of the Frenkel-Kontorova model is qualitatively similar to the behavior of similar models at nonzero temperature.Comment: Written in RevTeX, 13 figures in PostScript, appears in PR

Avalanches and the Renormalization Group for Pinned Charge-Density Waves

The critical behavior of charge-density waves (CDWs) in the pinned phase is studied for applied fields increasing toward the threshold field, using recently developed renormalization group techniques and simulations of automaton models. Despite the existence of many metastable states in the pinned state of the CDW, the renormalization group treatment can be used successfully to find the divergences in the polarization and the correlation length, and, to first order in an $\epsilon = 4-d$ expansion, the diverging time scale. The automaton models studied are a charge-density wave model and a ``sandpile'' model with periodic boundary conditions; these models are found to have the same critical behavior, associated with diverging avalanche sizes. The numerical results for the polarization and the diverging length and time scales in dimensions $d=2,3$ are in agreement with the analytical treatment. These results clarify the connections between the behaviour above and below threshold: the characteristic correlation lengths on both sides of the transition diverge with different exponents. The scaling of the distribution of avalanches on the approach to threshold is found to be different for automaton and continuous-variable models.Comment: 29 pages, 11 postscript figures included, REVTEX v3.0 (dvi and PS files also available by anonymous ftp from external.nj.nec.com in directory /pub/alan/cdwfigs