Translational development of difluoromethylornithine (DFMO) for the treatment of neuroblastoma

Neuroblastoma is a childhood tumor in which MYC oncogenes are commonly activated to drive tumor progression. Survival for children with high-risk neuroblastoma remains poor despite treatment that incorporates high-dose chemotherapy, stem cell support, surgery, radiation therapy and immunotherapy. More effective and less toxic treatments are sought and one approach under clinical development involves re-purposing the anti-protozoan drug difluoromethylornithine (DFMO; Eflornithine) as a neuroblastoma therapeutic. DFMO is an irreversible inhibitor of ornithine decarboxylase (Odc), a MYC target gene, bona fide oncogene, and the rate-limiting enzyme in polyamine synthesis. DFMO is approved for the treatment of Trypanosoma brucei gambiense encephalitis (“African sleeping sickness”) since polyamines are essential for the proliferation of these protozoa. However, polyamines are also critical for mammalian cell proliferation and the finding that MYC coordinately regulates all aspects of polyamine metabolism suggests polyamines may be required to support cancer promotion by MYC. Pre-emptive blockade of polyamine synthesis is sufficient to block tumor initiation in an otherwise fully penetrant transgenic mouse model of neuroblastoma driven by MYCN, underscoring the necessity of polyamines in this process. Moreover, polyamine depletion regimens exert potent anti-tumor activity in pre-clinical models of established neuroblastoma as well, in combination with numerous chemotherapeutic agents and even in tumors with unfavorable genetic features such as MYCN, ALK or TP53 mutation. This has led to the testing of DFMO in clinical trials for children with neuroblastoma. Current trial designs include testing lower dose DFMO alone (2,000 mg/m2/day) starting at the completion of standard therapy, or higher doses combined with chemotherapy (up to 9,000 mg/m2/day) for patients with relapsed disease that has progressed. In this review we will discuss important considerations for the future design of DFMO-based clinical trials for neuroblastoma, focusing on the need to better define the principal mechanisms of anti-tumor activity for polyamine depletion regimens. Putative DFMO activities that are both cancer cell intrinsic (targeting the principal oncogenic driver, MYC) and cancer cell extrinsic (altering the tumor microenvironment to support anti-tumor immunity) will be discussed. Understanding the mechanisms of DFMO activity are critical in determining how it might be best leveraged in upcoming clinical trials. This mechanistic approach also provides a platform by which iterative pre-clinical testing using translational tumor models may complement our clinical approaches

Enhancing the anti-angiogenic action of histone deacetylase inhibitors

<p>Abstract</p> <p>Background</p> <p>Histone deacetylase inhibitors (HDACIs) have many effects on cancer cells, such as growth inhibition, induction of cell death, differentiation, and anti-angiogenesis, all with a wide therapeutic index. However, clinical trials demonstrate that HDACIs are more likely to be effective when used in combination with other anticancer agents. Moreover, the molecular basis for the anti-cancer action of HDACIs is still unknown. In this study, we compared different combinations of HDACIs and anti-cancer agents with anti-angiogenic effects, and analysed their mechanism of action.</p> <p>Results</p> <p>Trichostatin A (TSA) and α-interferon (IFNα) were the most effective combination across a range of different cancer cell lines, while normal non-malignant cells did not respond in the same manner to the combination therapy. There was a close correlation between absence of basal p21^WAF1expression and response to TSA and IFNα treatment. Moreover, inhibition of p21^WAF1expression in a p21^WAF1-expressing breast cancer cell line by a specific siRNA increased the cytotoxic effects of TSA and IFNα. <it>In vitro </it>assays of endothelial cell function showed that TSA and IFNα decreased endothelial cell migration, invasion, and capillary tubule formation, without affecting endothelial cell viability. TSA and IFNα co-operatively inhibited gene expression of some pro-angiogenic factors: vascular endothelial growth factor, hypoxia-inducible factor 1α and matrix metalloproteinase 9, in neuroblastoma cells under hypoxic conditions. Combination TSA and IFNα therapy markedly reduced tumour angiogenesis in neuroblastoma-bearing transgenic mice.</p> <p>Conclusion</p> <p>Our results indicate that combination TSA and IFNα therapy has potent co-operative cytotoxic and anti-angiogenic activity. High basal p21^WAF1expression appears to be acting as a resistance factor to the combination therapy.</p

Procedural justice, compliance with the law and police stop-and-search: a study of young people in England and Scotland

The policing of young people, especially through stop-and-search, has been rigorously debated in the context of rising violence in the UK. While concepts based on procedural justice theory and perceptions of police fairness are directly relevant to these debates, these have rarely been tested on young people, nor have they taken account of the impact of stop-and-search. This paper examines young people’s experiences of stop-and-search in two Scottish and two English cities, and tests the relationship between these experiences, their trust in the police, their perceptions of police legitimacy and their compliance with the law. The study finds that Scottish adolescents, who experienced higher volume stop-and-search, had more negative attitudes to the police and perceived them to be less procedurally fair than English adolescents. Structural equation modelling confirms that principles of procedural justice theory do apply to young people in this UK sample. However, our findings suggest that stop-and-search may damage trust in the police and perceptions of police legitimacy, regardless of the volume of police stop-and-search, and this may result in increased offending behaviour. With ongoing calls to increase the use of stop-and-search in response to recent increases in knife crime in England, we argue that its use needs to be carefully balanced against the, as yet poorly evidenced, benefits of the use of the tactic

Interchanging Interactive 3-d Graphics for Astronomy

We demonstrate how interactive, three-dimensional (3-d) scientific visualizations can be efficiently interchanged between a variety of mediums. Through the use of an appropriate interchange format, and a unified interaction interface, we minimize the effort to produce visualizations appropriate for undertaking knowledge discovery at the astronomer's desktop, as part of conference presentations, in digital publications or as Web content. We use examples from cosmological visualization to address some of the issues of interchange, and to describe our approach to adapting S2PLOT desktop visualizations to the Web. Supporting demonstrations are available at http://astronomy.swin.edu.au/s2plot/interchange/Comment: 10 pages, 7 figures, submitted to Publications of the Astronomical Society of Australia. v2. Revised title, revised figure 1, fixed typos, minor additions to future work sectio

Macrophage-derived IL-1β and TNF-α regulate arginine metabolism in neuroblastoma

© 2018 American Association for Cancer Research. Neuroblastoma is the most common childhood solid tumor, yet the prognosis for high-risk disease remains poor. We demonstrate here that arginase 2 (ARG2) drives neuroblastoma cell proliferation via regulation of arginine metabolism. Targeting arginine metabolism, either by blocking cationic amino acid transporter 1 (CAT-1)-dependent arginine uptake in vitro or therapeutic depletion of arginine by pegylated recombinant arginase BCT-100, significantly delayed tumor development and prolonged murine survival. Tumor cells polarized infiltrating monocytes to an M1-macrophage phenotype, which released IL1b and TNFa in a RAC-alpha serine/threonine-protein kinase (AKT)-dependent manner. IL1b and TNFa established a feedback loop to upregulate ARG2 expression via p38 and extracellular regulated kinases 1/2 (ERK1/2) signaling in neuroblastoma and neural crest-derived cells. Proteomic analysis revealed that enrichment of IL1b and TNFa in stage IV human tumor microenvironments was associated with a worse prognosis. These data thus describe an immune-metabolic regulatory loop between tumor cells and infiltrating myeloid cells regulating ARG2, which can be clinically exploited

Geochemical analysis of bulk marine sediment by Inductively Coupled Plasma–Atomic Emission Spectroscopy on board the JOIDES Resolution

Geochemical analyses on board the JOIDES Resolution have been enhanced with the addition of a Jobin-Yvon Ultrace inductively coupled plasma-atomic emission spectrometer (ICP-AES) as an upgrade from the previous X-ray fluorescence facility. During Leg 199, we sought to both challenge and utilize the capabilities of the ICP-AES in order to provide an extensive bulk-sediment geochemical database during the cruise. These near real-time analyses were then used to help characterize the recovered sedimentary sequences, calculate mass accumulation rates of the different sedimentary components, and assist with cruise and postcruise sampling requests. The general procedures, sample preparation techniques, and basic protocol for ICP-AES analyses on board ship are outlined by Murray et al. (2000) in Ocean Drilling Program Tech Note, 29. We expand on those concepts and offer suggestions for ICP-AES methodology, calibration by standard reference materials, data reduction procedures, and challenges that are specific to the analysis of bulk-sediment samples. During Leg 199, we employed an extensive bulk-sediment analytical program of ~600 samples of varying lithologies, thereby providing several opportunities for refinement of techniques. We also discuss some difficulties and challenges that were faced and suggest how to alleviate such occurrences for sedimentary chemical analyses during future legs

Variations in the Galactic star formation rate and density thresholds for star formation

The conversion of gas into stars is a fundamental process in astrophysics and cosmology. Stars are known to form from the gravitational collapse of dense clumps in interstellar molecular clouds, and it has been proposed that the resulting star formation rate is proportional to either the amount of mass above a threshold gas surface density, or the gas volume density. These star-formation prescriptions appear to hold in nearby molecular clouds in our Milky Way Galaxy's disk as well as in distant galaxies where the star formation rates are often much larger. The inner 500 pc of our Galaxy, the Central Molecular Zone (CMZ), contains the largest concentration of dense, high-surface density molecular gas in the Milky Way, providing an environment where the validity of star-formation prescriptions can be tested. Here we show that by several measures, the current star formation rate in the CMZ is an order-of-magnitude lower than the rates predicted by the currently accepted prescriptions. In particular, the region 1 deg < l < 3.5 deg, |b| < 0.5 deg contains ~10^7 Msun of dense molecular gas -- enough to form 1000 Orion-like clusters -- but the present-day star formation rate within this gas is only equivalent to that in Orion. In addition to density, another property of molecular clouds, such as the amplitude of turbulent motions, must be included in the star-formation prescription to predict the star formation rate in a given mass of molecular gas.Comment: 17 pages, 6 figures, submitted MNRA

Centrality dependence of charged-particle pseudorapidity distributions from d+Au collisions at sqrt(s_{NN})=200 GeV

Charged-particle pseudorapidity densities are presented for the d+Au reaction at sqrt{s_{NN}}=200 GeV with -4.2 <= eta <= 4.2$. The results, from the BRAHMS experiment at RHIC, are shown for minimum-bias events and 0-30%, 30-60%, and 60-80% centrality classes. Models incorporating both soft physics and hard, perturbative QCD-based scattering physics agree well with the experimental results. The data do not support predictions based on strong-coupling, semi-classical QCD. In the deuteron-fragmentation region the central 200 GeV data show behavior similar to full-overlap d+Au results at sqrt{s_{NN}}=19.4 GeV.Comment: 4 pages, 3figures; expanded discussion of uncertainties; added 60-80% centrality range; added additional discussion on centrality selection bia