Mathematical Model of Clonal Evolution Proposes a Personalised Multi-Modal Therapy for High-Risk Neuroblastoma

: Neuroblastoma is the most common extra-cranial solid tumour in children. Despite multi-modal therapy, over half of the high-risk patients will succumb. One contributing factor is the one-size-fits-all nature of multi-modal therapy. For example, during the first step (induction chemotherapy), the standard regimen (rapid COJEC) administers fixed doses of chemotherapeutic agents in eight two-week cycles. Perhaps because of differences in resistance, this standard regimen results in highly heterogeneous outcomes in different tumours. In this study, we formulated a mathematical model comprising ordinary differential equations. The equations describe the clonal evolution within a neuroblastoma tumour being treated with vincristine and cyclophosphamide, which are used in the rapid COJEC regimen, including genetically conferred and phenotypic drug resistance. The equations also describe the agents' pharmacokinetics. We devised an optimisation algorithm to find the best chemotherapy schedules for tumours with different pre-treatment clonal compositions. The optimised chemotherapy schedules exploit the cytotoxic difference between the two drugs and intra-tumoural clonal competition to shrink the tumours as much as possible during induction chemotherapy and before surgical removal. They indicate that induction chemotherapy can be improved by finding and using personalised schedules. More broadly, we propose that the overall multi-modal therapy can be enhanced by employing targeted therapies against the mutations and oncogenic pathways enriched and activated by the chemotherapeutic agents. To translate the proposed personalised multi-modal therapy into clinical use, patient-specific model calibration and treatment optimisation are necessary. This entails a decision support system informed by emerging medical technologies such as multi-region sequencing and liquid biopsies. The results and tools presented in this paper could be the foundation of this decision support system

Determination of the eta'-proton scattering length in free space

Taking advantage of both the high mass resolution of the COSY-11 detector and the high energy resolution of the low-emittance proton-beam of the Cooler Synchrotron COSY we determine the excitation function for the pp --> pp eta' reaction close-to-threshold. Combining these data with previous results we extract the scattering length for the eta'-proton potential in free space to be Re(a_{p eta'}) = 0+-0.43 fm and Im(a_{p eta'}) = 0.37(+0.40)(-0.16) fm.Comment: 5 pages, 3 figures, accepted for publication in Phys. Rev. Let

The essential peptidoglycan glycosyltransferase MurG forms a complex with proteins involved in lateral envelope growth as well as with proteins involved in cell division in Escherichia coli

In Escherichia coli many enzymes including MurG are directly involved in the synthesis and assembly of peptidoglycan. MurG is an essential glycosyltransferase catalysing the last intracellular step of peptidoglycan synthesis. To elucidate its role during elongation and division events, localization of MurG using immunofluorescence microscopy was performed. MurG exhibited a random distribution in the cell envelope with a relatively higher intensity at the division site. This mid-cell localization was dependent on the presence of a mature divisome. Its localization in the lateral cell wall appeared to require the presence of MreCD. This could be indicative of a potential interaction between MurG and other proteins. Investigating this by immunoprecipitation revealed the association of MurG with MreB and MraY in the same protein complex. In view of this, the loss of rod shape of ΔmreBCD strain could be ascribed to the loss of MurG membrane localization. Consequently, this could prevent the localized supply of the lipid II precursor to the peptidoglycan synthesizing machinery involved in cell elongation. It is postulated that the involvement of MurG in the peptidoglycan synthesis concurs with two complexes, one implicated in cell elongation and the other in division. A model representing the first complex is proposed

General thoughts to the Kaon pair production in the threshold region

Simple--minded thoughts about the cross sections for the reactions pp-->ppK+K- and pp-->ppK0K0 are presented, which certainly do not account for the complex coupled channel problem but rather provide some ideas into the mutual reaction dynamics.Comment: Talk given at 9th International Workshop on Meson Production, Properties and Interaction, Cracow, Poland, 9-13 June 2006. 3 pages, 2 figure

Associated strangeness production in pp collisions near threshold

Motivated by the ongoing discussion concerning the nature of the scalar resonances f0(980) and a0(980), the COSY-11 collaboration has taken exclusive data on the pp->ppK+K- reaction near the production threshold. A first total cross section sigma=(1.80+-0.27+0.28-0.35)nb for the excess energy Q=17 MeV has been determined. In contrary to the eta, omega and eta' single meson production studies which clearly show the strong pp final state interaction (FSI), the cross section values obtained at COSY-11 and DISTO can be both described by a fit with a four-body phase space including the proton-proton final state interaction as well as with one-meson exchange calculations neglecting FSI effects. Therefore, one might think about a compensation of the strong pp interaction through a pK- FSI effect or an additional degree of freedom caused by the four-body final state. In the latter case, strong FSI effects can be expected at Q-values very close to the K+K- production threshold. Such a motivation triggered -- in combination with the investigation of the kaon-Antikaon interaction being relevant to the structure of the f0(980) -- further measurements at the excess energies Q=10 and Q=28 MeV at COSY-11.Comment: 5 pages, 4 figures, Presented at X. International Conference On Hadron Spectroscopy (Hadron 2003), Aschaffenburg, Germany, 31 Aug - 6 Sep 200

Dynamics of the near threshold eta meson production in proton-proton interaction

We present the results of measurements of the analysing power for the p(pol)p --> pp eta reaction at the excess energies of Q=10 and 36 MeV, and interpret these results within the framework of the meson exchange models. The determined values of the analysing power at both excess energies are consistent with zero implying that the eta meson is produced predominantly in s-wave.Comment: 3 pages, 3 figures, Presented at the Workshop on the physics of excited nucleons (NSTAR 2007), 5-8 September 2007, Bonn, German

First close-to-threshold measurement of the analyzing power Ay in the reaction p(pol)p -> pp eta

At the internal facility COSY-11 a first measurement of the reaction p(pol)p -> pp eta near the production threshold has been performed. Results for the analysing power will be presented and a comparison with one meson exchange models will be discussed.Comment: 3 pages, 3 figures, Presented at Conference on Quarks and Nuclear Physics (QNP 2002), Julich, Germany, 9-14 Jun 200

Production of eta and eta-prime mesons via the quasi-free proton-neutron interaction

A comparison of the close-to-threshold total cross sections for the eta-prime meson production in both the pp --> pp eta-prime and pn --> pn eta-prime reactions should provide insight into the flavour-singlet (perhaps also into gluonium) content of the eta-prime meson and the relevance of quark-gluon or hadronic degrees of freedom in the creation process. The excitation function for the reaction pp --> pp eta-prime has been already established. At present, experimental investigations of the quasi-free pn --> pn X reactions are carried out at the COSY-11 facility using a beam of stochastically cooled protons and the deuteron cluster target. A method of measurement and preliminary results from the test experiments of the pn --> pn eta reaction are presented in this report.Comment: 5 pages, 5 figures, Presented at X. International Conference On Hadron Spectroscopy (Hadron 2003), Aschaffenburg, Germany, 31 Aug - 6 Sep 200

IFT proteins interact with HSET to promote supernumerary centrosome clustering in mitosis.

Centrosome amplification is a hallmark of cancer, and centrosome clustering is essential for cancer cell survival. The mitotic kinesin HSET is an essential contributor to this process. Recent studies have highlighted novel functions for intraflagellar transport (IFT) proteins in regulating motors and mitotic processes. Here, using siRNA knock-down of various IFT proteins or AID-inducible degradation of endogenous IFT88 in combination with small-molecule inhibition of HSET, we show that IFT proteins together with HSET are required for efficient centrosome clustering. We identify a direct interaction between the kinesin HSET and IFT proteins, and we define how IFT proteins contribute to clustering dynamics during mitosis using high-resolution live imaging of centrosomes. Finally, we demonstrate the requirement of IFT88 for efficient centrosome clustering in a variety of cancer cell lines naturally harboring supernumerary centrosomes and its importance for cancer cell proliferation. Overall, our data unravel a novel role for the IFT machinery in centrosome clustering during mitosis in cells harboring supernumerary centrosomes

Total and Differential Cross Sections for the pp-->pp eta-prime Reaction Near Threshold

The eta-prime meson production in the reaction pp-->pp eta-prime has been studied at excess energies of Q = 26.5, 32.5 and 46.6 MeV using the internal beam facility COSY-11 at the cooler synchrotron COSY. The total cross sections as well as one angular distribution for the highest Q-value are presented. The excitation function of the near threshold data can be described by a pure s-wave phase space distribution with the inclusion of the proton-proton final state interaction and Coulomb effects. The obtained angular distribution of the eta-prime mesons is also consistent with pure s-wave production.Comment: 6 pages, 5 figures, submitted to Eur. Phys. J.