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

A Documentation of the Videography Process for Maintaining the Mountains: The Preservation of Appalachian Music

A thesis presented to the faculty of the Caudill College of Humanities at Morehead State University in partial fulfillment of the requirements for the Degree of Master of Arts by Steven 0. Middleton in May of 2008

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

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

Biological response to circulation driven by mean summertime winds off central Chile: A numerical model study

A coupled physical-biological model of the waters off central Chile is used to investigate the nitrogen-phytoplankton-zooplankton response to ocean circulation driven by mean summertime winds. The circulation drives the upwelling of middepth water onto the continental shelf and reaches a quasistable rate between days 40 and 60 of the simulation. High-nutrient, low-phytoplankton biomass water is upwelled at the coast, with nutrients being converted to phytoplankton within 3-10 days. A lagged response in zooplankton occurs after 6-30 days, by which time the water has been advected offshore. The magnitude and spatial distribution of phytoplankton biomass and export of organic matter off the continental shelf is sensitive to the zooplankton mortality term. For low zooplankton mortality, phytoplankton biomass on the continental shelf is limited by grazing pressure due to zooplankton, phytoplankton and zooplankton biomass remains low, and the nitrogen advected off the continental shelf in the surface waters is primarily dissolved inorganic nitrogen. When the mortality rate is increased fourfold, an approximately fourfold to fivefold increase is seen in the continental shelf phytoplankton biomass, phytoplankton productivity, and export of organic matter to the deep ocean. This dependence on zooplankton mortality illustrates the potential of top-down control of the shelf production and export of organic matter off the central Chile continental shelf. Copyright 2007 by the American Geophysical Union

Complement deficiencies limit CD20 monoclonal antibody treatment efficacy in CLL

Monoclonal antibodies (MAbs) form a central part of chronic lymphocytic leukaemia (CLL) treatment. We therefore evaluated whether complement defects in CLL patients reduced the induction of complement-dependent cytotoxicity (CDC) by using anti-CD20 MAbs rituximab (RTX) and ofatumumab (OFA). Ofatumumab elicited higher CDC levels than RTX in all CLL samples examined, particularly in poor prognosis cohorts (11q− and 17p−). Serum sample analyses revealed that 38.1% of patients were deficient in one or more complement components, correlating with reduced CDC responses. Although a proportion of patients with deficient complement levels initially induced high levels of CDC, on secondary challenge CDC activity in sera was significantly reduced, compared with that in normal human serum (NHS; P<0.01; n=52). In addition, a high CLL cell number contributed to rapid complement exhaustion. Supplementing CLL serum with NHS or individual complement components, particularly C2, restored CDC on secondary challenge to NHS levels (P<0.0001; n=9). In vivo studies revealed that complement components were exhausted in CLL patient sera post RTX treatment, correlating with an inability to elicit CDC. Supplementing MAb treatment with fresh-frozen plasma may therefore maintain CDC levels in CLL patients with a complement deficiency or high white blood cell count. This study has important implications for CLL patients receiving anti-CD20 MAb therapy

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

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

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