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

Gauge invariant definition of the jet quenching parameter

In the framework of Soft-Collinear Effective Theory, the jet quenching parameter, $\hat{q}$, has been evaluated by adding the effect of Glauber gluon interactions to the propagation of a highly-energetic collinear parton in a medium. The result, which holds in covariant gauges, has been expressed in terms of the expectation value of two Wilson lines stretching along the direction of the four-momentum of the parton. In this paper, we show how that expression can be generalized to an arbitrary gauge by the addition of transverse Wilson lines. The transverse Wilson lines are explicitly computed by resumming interactions of the parton with Glauber gluons that appear only in non-covariant gauges. As an application of our result, we discuss the contribution to $\hat{q}$ coming from transverse momenta of order $g^2T$ in a medium that is a weakly-coupled quark-gluon plasma.Comment: 31 pages, 7 figures; journal versio

Time and dose dependency of bone-sarcomas in patients injected with radium-224

The time course and dose dependency of the incidence of bone-sarcomas among 900 German patients treated with high doses of radium-224 is analysed in terms of a proportional hazards model with a log-normal dependency of time to tumor and a linear-quadratic dose relation. The deduced dose dependency agrees well with a previous analysis in terms of a non-parametric proportional hazards model, and confirms the temporal distribution which has been used in the Radioepidemiological Tables of NIH. However, the linear-quadratic dose-response model gives a risk estimate for low doses which is somewhat less than half that obtained under the assumption of linearity. Dedicated to Prof. W. Jacobi on the occasion of his 60th birthday Work performed under Euratom contracts BI6-D-083-D, BI6-F-111-D, U.S. Department of Energy contract DE-AC 02-76 EV-00119, the U.S. National Cancer Institut

Non-global Structure of the O({\alpha}_s^2) Dijet Soft Function

High energy scattering processes involving jets generically involve matrix elements of light- like Wilson lines, known as soft functions. These describe the structure of soft contributions to observables and encode color and kinematic correlations between jets. We compute the dijet soft function to O({\alpha}_s^2) as a function of the two jet invariant masses, focusing on terms not determined by its renormalization group evolution that have a non-separable dependence on these masses. Our results include non-global single and double logarithms, and analytic results for the full set of non-logarithmic contributions as well. Using a recent result for the thrust constant, we present the complete O({\alpha}_s^2) soft function for dijet production in both position and momentum space.Comment: 55 pages, 8 figures. v2: extended discussion of double logs in the hard regime. v3: minor typos corrected, version published in JHEP. v4: typos in Eq. (3.33), (3.39), (3.43) corrected; this does not affect the main result, numerical results, or conclusion

Jet Shapes and Jet Algorithms in SCET

Jet shapes are weighted sums over the four-momenta of the constituents of a jet and reveal details of its internal structure, potentially allowing discrimination of its partonic origin. In this work we make predictions for quark and gluon jet shape distributions in N-jet final states in e+e- collisions, defined with a cone or recombination algorithm, where we measure some jet shape observable on a subset of these jets. Using the framework of Soft-Collinear Effective Theory, we prove a factorization theorem for jet shape distributions and demonstrate the consistent renormalization-group running of the functions in the factorization theorem for any number of measured and unmeasured jets, any number of quark and gluon jets, and any angular size R of the jets, as long as R is much smaller than the angular separation between jets. We calculate the jet and soft functions for angularity jet shapes \tau_a to one-loop order (O(alpha_s)) and resum a subset of the large logarithms of \tau_a needed for next-to-leading logarithmic (NLL) accuracy for both cone and kT-type jets. We compare our predictions for the resummed \tau_a distribution of a quark or a gluon jet produced in a 3-jet final state in e+e- annihilation to the output of a Monte Carlo event generator and find that the dependence on a and R is very similar.Comment: 62 pages plus 21 pages of Appendices, 13 figures, uses JHEP3.cls. v2: corrections to finite parts of NLO jet functions, minor changes to plots, clarified discussion of power corrections. v3: Journal version. Introductory sections significantly reorganized for clarity, classification of logarithmic accuracy clarified, results for non-Mercedes-Benz configurations adde

Direct photon production with effective field theory

The production of hard photons in hadronic collisions is studied using Soft-Collinear Effective Theory (SCET). This is the first application of SCET to a physical, observable cross section involving energetic partons in more than two directions. A factorization formula is derived which involves a non-trivial interplay of the angular dependence in the hard and soft functions, both quark and gluon jet functions, and multiple partonic channels. The relevant hard, jet and soft functions are computed to one loop and their anomalous dimensions are determined to three loops. The final resummed inclusive direct photon distribution is valid to next-to-next-to-leading logarithmic order (NNLL), one order beyond previous work. The result is improved by including non-logarithmic terms and photon isolation cuts through matching, and compared to Tevatron data and to fixed order results at the Tevatron and the LHC. The resummed cross section has a significantly smaller theoretical uncertainty than the next-to-leading fixed-order result, particularly at high transverse momentum.Comment: 42 pages, 9 figures; v2: references added, minor changes; v3: typos; v4: typos, corrections in (16), (47), (72

An effective theory for jet propagation in dense QCD matter: jet broadening and medium-induced bremsstrahlung

Two effects, jet broadening and gluon bremsstrahlung induced by the propagation of a highly energetic quark in dense QCD matter, are reconsidered from effective theory point of view. We modify the standard Soft Collinear Effective Theory (SCET) Lagrangian to include Glauber modes, which are needed to implement the interactions between the medium and the collinear fields. We derive the Feynman rules for this Lagrangian and show that it is invariant under soft and collinear gauge transformations. We find that the newly constructed theory SCET$_{\rm G}$ recovers exactly the general result for the transverse momentum broadening of jets. In the limit where the radiated gluons are significantly less energetic than the parent quark, we obtain a jet energy-loss kernel identical to the one discussed in the reaction operator approach to parton propagation in matter. In the framework of SCET$_{\rm G}$ we present results for the fully-differential bremsstrahlung spectrum for both the incoherent and the Landau-Pomeranchunk-Migdal suppressed regimes beyond the soft-gluon approximation. Gauge invariance of the physics results is demonstrated explicitly by performing the calculations in both the light-cone and covariant $R_{\xi}$ gauges. We also show how the process-dependent medium-induced radiative corrections factorize from the jet production cross section on the example of the quark jets considered here.Comment: 52 pages, 15 pdf figures, as published in JHE

Resummation of heavy jet mass and comparison to LEP data

The heavy jet mass distribution in e+e- collisions is computed to next-to-next-to-next-to leading logarithmic (NNNLL) and next-to-next-to leading fixed order accuracy (NNLO). The singular terms predicted from the resummed distribution are confirmed by the fixed order distributions allowing a precise extraction of the unknown soft function coefficients. A number of quantitative and qualitative comparisons of heavy jet mass and the related thrust distribution are made. From fitting to ALEPH data, a value of alpha_s is extracted, alpha_s(m_Z)=0.1220 +/- 0.0031, which is larger than, but not in conflict with, the corresponding value for thrust. A weighted average of the two produces alpha_s(m_Z) = 0.1193 +/- 0.0027, consistent with the world average. A study of the non-perturbative corrections shows that the flat direction observed for thrust between alpha_s and a simple non-perturbative shape parameter is not lifted in combining with heavy jet mass. The Monte Carlo treatment of hadronization gives qualitatively different results for thrust and heavy jet mass, and we conclude that it cannot be trusted to add power corrections to the event shape distributions at this accuracy. Whether a more sophisticated effective field theory approach to power corrections can reconcile the thrust and heavy jet mass distributions remains an open question.Comment: 33 pages, 14 figures. v2 added effect of lower numerical cutoff with improved extraction of the soft function constants; power correction discussion clarified. v3 small typos correcte

Parton Fragmentation within an Identified Jet at NNLL

The fragmentation of a light parton i to a jet containing a light energetic hadron h, where the momentum fraction of this hadron as well as the invariant mass of the jet is measured, is described by "fragmenting jet functions". We calculate the one-loop matching coefficients J_{ij} that relate the fragmenting jet functions G_i^h to the standard, unpolarized fragmentation functions D_j^h for quark and gluon jets. We perform this calculation using various IR regulators and show explicitly how the IR divergences cancel in the matching. We derive the relationship between the coefficients J_{ij} and the quark and gluon jet functions. This provides a cross-check of our results. As an application we study the process e+ e- to X pi+ on the Upsilon(4S) resonance where we measure the momentum fraction of the pi+ and restrict to the dijet limit by imposing a cut on thrust T. In our analysis we sum the logarithms of tau=1-T in the cross section to next-to-next-to-leading-logarithmic accuracy (NNLL). We find that including contributions up to NNLL (or NLO) can have a large impact on extracting fragmentation functions from e+ e- to dijet + h.Comment: expanded introduction, typos fixed, journal versio

A prospective analysis of the injury incidence of young male professional football players on artificial turf

Background: The effects of synthetic surfaces on the risk of injuries is still debated in literature and the majority of published data seems to be contradictory. For such reasons the understanding of injury incidence on such surfaces, especially in youth sport, is fundamental for injury prevention. Objectives: The aim of this study was to prospectively report the epidemiology of injuries in young football players, playing on artificial turfs, during a one sports season. Patients and Methods: 80 young male football players (age 16.1 ± 3.7 years; height 174 ± 6.6 cm; weight 64.2 ± 6.3 kg) were enrolled in a prospective cohort study. The participants were then divided in two groups; the first included players age ranging from 17 to 19 (OP) whereas the second included players age ranging from 13 to 16 (YP). Injury incidence was recorded prospectively, according to the consensus statement for soccer. Results: A total of 107 injuries (35 from the OP and 72 from the YP) were recorded during an exposure time of 83.760 hours (incidence 1.28/1000 per player hours); 22 during matches (incidence 2.84/1000 per player hours, 20.5%) and 85 during training (incidence 1.15/1000 per player hours, 79.5%). Thigh and groin were the most common injury locations (33.6% and 21.5%, respectively) while muscle injuries such as contractures and strains were the most common injury typologies (68.23%). No statistical differences between groups were displayed, except for the rate of severe injuries during matches, with the OP displaying slightly higher rates compared to the YP. Severe injuries accounted for 10.28% of the total injuries reported. The average time lost due to injuries was 14 days. Re-injuries accounted for 4.67% of all injuries sustained during the season. Conclusions: In professional youth soccer injury rates are reasonably low. Muscle injuries are the most common type of injuries while groin and thigh the most common locations. Artificial turf pitches don’t seem to contribute to injury incidence in young football players