Profiling lung adenocarcinoma by liquid biopsy: can one size fit all?

BACKGROUND: Cancer is first and foremost a disease of the genome. Specific genetic signatures within a tumour are prognostic of disease outcome, reflect subclonal architecture and intratumour heterogeneity, inform treatment choices and predict the emergence of resistance to targeted therapies. Minimally invasive liquid biopsies can give temporal resolution to a tumour's genetic profile and allow the monitoring of treatment response through levels of circulating tumour DNA (ctDNA). However, the detection of ctDNA in repeated liquid biopsies is currently limited by economic and time constraints associated with targeted sequencing. METHODS: Here we bioinformatically profile the mutational and copy number spectrum of The Cancer Genome Network's lung adenocarcinoma dataset to uncover recurrently mutated genomic loci. RESULTS: We build a panel of 400 hotspot mutations and show that the coverage extends to more than 80% of the dataset at a median depth of 8 mutations per patient. Additionally, we uncover several novel single-nucleotide variants present in more than 5% of patients, often in genes not commonly associated with lung adenocarcinoma. CONCLUSION: With further optimisation, this hotspot panel could allow molecular diagnostics laboratories to build curated primer banks for 'off-the-shelf' monitoring of ctDNA by droplet-based digital PCR or similar techniques, in a time- and cost-effective manner

Object-oriented Programming Laws for Annotated Java Programs

Object-oriented programming laws have been proposed in the context of languages that are not combined with a behavioral interface specification language (BISL). The strong dependence between source-code and interface specifications may cause a number of difficulties when transforming programs. In this paper we introduce a set of programming laws for object-oriented languages like Java combined with the Java Modeling Language (JML). The set of laws deals with object-oriented features taking into account their specifications. Some laws deal only with features of the specification language. These laws constitute a set of small transformations for the development of more elaborate ones like refactorings

Abundance of Delta Resonances in 58Ni+58Ni Collisions between 1 and 2 AGeV

Charged pion spectra measured in 58Ni-58Ni collisions at 1.06, 1.45 and 1.93 AGeV are interpreted in terms of a thermal model including the decay of Delta resonances. The transverse momentum spectra of pions are well reproduced by adding the pions originating from the Delta-resonance decay to the component of thermal pions, deduced from the high transverse momentum part of the pion spectra. About 10 and 18% of the nucleons are excited to Delta states at freeze-out for beam energies of 1 and 2 AGeV, respectively.Comment: 14 pages, LaTeX with 3 included figures; submitted to Physics Letters

Strange meson production in Al+Al collisions at 1.9A GeV

The production of K$^+$, K$^-$ and $\varphi$(1020) mesons is studied in Al+Al collisions at a beam energy of 1.9A GeV which is close or below the production threshold in NN reactions. Inverse slopes, anisotropy parameters, and total emission yields of K$^{\pm}$ mesons are obtained. A comparison of the ratio of kinetic energy distributions of K$^-$ and K$^+$ mesons to the HSD transport model calculations suggests that the inclusion of the in-medium modifications of kaon properties is necessary to reproduce the ratio. The inverse slope and total yield of $\phi$ mesons are deduced. The contribution to K$^-$ production from $\phi$ meson decays is found to be [17 $\pm$ 3 (stat) $^{+2}_{-7}$ (syst)] %. The results are in line with previous K$^{\pm}$ and $\phi$ data obtained for different colliding systems at similar incident beam energies.Comment: 16 pages, 11 figure

Centrality dependence of subthreshold ϕ\phi meson production in Ni+Ni collisions at 1.9A GeV

We analysed the $\phi$ meson production in central Ni+Ni collisions at the beam kinetic energy of 1.93A GeV with the FOPI spectrometer and found the production probability per event of $[8.6 ~\pm~ 1.6 ~(\text{stat}) \pm 1.5 ~(\text{syst})] \times 10^{-4}$. This new data point allows for the first time to inspect the centrality dependence of the subthreshold $\phi$ meson production in heavy-ion collisions. The rise of $\phi$ meson multiplicity per event with mean number of participants can be parameterized by the power function with exponent $\alpha = 1.8 \pm 0.6$. The ratio of $\phi$ to $\text{K}^-$ production yields seems not to depend within the experimental uncertainties on the collision centrality, and the average of measured values was found to be $0.36 \pm 0.05$.Comment: 9 pages, 5 figure

Stopping and Radial Flow in Central 58Ni + 58Ni Collisions between 1 and 2 AGeV

The production of charged pions, protons and deuterons has been studied in central collisions of 58Ni on 58Ni at incident beam energies of 1.06, 1.45 and 1.93 AGeV. The dependence of transverse-momentum and rapidity spectra on the beam energy and on the centrality of the collison is presented. It is shown that the scaling of the mean rapidity shift of protons established for AGS and SPS energies is valid down to 1 AGeV. The degree of nuclear stopping is discussed; the IQMD transport model reproduces the measured proton rapidity spectra for the most central events reasonably well, but does not show any sensitivity between the soft and the hard equation of state (EoS). A radial flow analysis, using the midrapidity transverse-momentum spectra, delivers freeze-out temperatures T and radial flow velocities beta_r which increase with beam energy up to 2 AGeV; in comparison to existing data of Au on Au over a large range of energies only beta_r shows a system size dependence

Isospin dependence of relative yields of K+K^+ and K0K^0 mesons at 1.528 AGeV

Results on $K^+$ and $K^0$ meson production in $^{96}_{44}$Ru + $^{96}_{44}$Ru and $^{96}_{40}$Zr + $^{96}_{40}$Zr collisions at a beam kinetic energy of 1.528$A$ GeV, measured with the FOPI detector at GSI-Darmstadt, are investigated as a possible probe of isospin effects in high density nuclear matter. The measured double ratio ($K^+/K^0$)$_{Ru}$/($K^+/K^0$)$_{Zr}$ is compared to the predictions of a thermal model and a Relativistic Mean Field transport model using two different collision scenarios and under different assumptions on the stiffness of the symmetry energy. We find a good agreement with the thermal model prediction and the assumption of a soft symmetry energy for infinite nuclear matter while more realistic transport simulations of the collisions show a similar agreement with the data but also exhibit a reduced sensitivity to the symmetry term.Comment: 5 pages, 3 figures. accepted for publication in Phys. Rev.

Two-proton small-angle correlations in central heavy-ion collisions: a beam-energy and system-size dependent study

Small-angle correlations of pairs of protons emitted in central collisions of Ca + Ca, Ru + Ru and Au + Au at beam energies from 400 to 1500 MeV per nucleon are investigated with the FOPI detector system at SIS/GSI Darmstadt. Dependences on system size and beam energy are presented which extend the experimental data basis of pp correlations in the SIS energy range substantially. The size of the proton-emitting source is estimated by comparing the experimental data with the output of a final-state interaction model which utilizes either static Gaussian sources or the one-body phase-space distribution of protons provided by the BUU transport approach. The trends in the experimental data, i.e. system-size and beam energy dependences, are well reproduced by this hybrid model. However, the pp correlation function is found rather insensitive to the stiffness of the equation of state entering the transport model calculations.Comment: 9 pages, 8 figures, accepted at Eur. Phys. Journ.

Measurement of K∗(892)0K^*(892)^0 and K0K^0 mesons in Al+Al collisions at 1.9AA GeV

New measurement of sub-threshold $K^*(892)^0$ and $K^0$ production is presented. The experimental data complete the measurement of strange particles produced in Al+Al collisions at 1.9$A$ GeV measured with the FOPI detector at SIS/GSI. The $K^*(892)^0$ / $K^0$ yield ratio is found to be $0.0315\pm 0.006 (\mathrm{stat.})\pm 0.012 (\mathrm{syst.})$ and is in good agreement with the UrQMD model prediction. These measurements provide information on in-medium cross section of $K^+$ - $\pi^-$ fusion which is the dominant process on sub-threshold $K^*(892)^0$ production.Comment: 5 pages, 4 figures, accepted for publication in Phys. Rev.