Using computing models from particle physics to investigate dose-toxicity correlations in cancer radiotherapy

© Published under licence by IOP Publishing Ltd. A system has been developed to provide flexible, efficient and robust processing of radiotherapy planning and treatment data collected in the VoxTox project, which investigates differences between planned and delivered dose, and dose-toxicity correlations. This paper outlines the system requirements and implementation, highlighting the use made of software tools and computing models developed for experiments at the Large Hadron Collider. Experience with VoxTox data processing is summarised

Comparative expression pattern of Matrix-Metalloproteinases in human glioblastoma cell-lines and primary cultures

<p>Abstract</p> <p>Background</p> <p>Glioblastomas (GBM), the most frequent malignant brain tumors in adults, are characterized by an aggressive local growth pattern and highly invasive tumor cells. This invasion is facilitated by expression of matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases. They mediate the degradation of protein components of the extracellular matrix. Twenty-three family members are known. Elevated levels of several of them have been reported in GBM. GBM cell-lines are used for <it>in vitro </it>studies of cell migration and invasion. Therefore, it is essential to know their MMP expression patterns. Only limited data for some of the cell-lines are published, yet. To fill the gaps in our knowledge would help to choose suitable model systems for analysis of regulation and function of MMPs during GBM tumorigenesis, cell migration and invasion.</p> <p>Findings</p> <p>We analysed MMP-1, -8, -9, -10, -11, -13, -17, -19, -20, -21, -23, -24, -26, -27, and MMP-28 expression in seven GBM cell-lines (SNB-19, GaMG, U251, U87, U373, U343, U138) and in four primary cell cultures by semiquantitative RT-PCR, followed changes in the MMP expression pattern with increasing passages of cell culture and examined the influence of TNF-α and TGF-β1 stimulation on the expression of selected MMPs in U251 and U373 cells.</p> <p>MMP-13, -17, -19 and -24 were expressed by all analyzed cell-lines, whereas MMP-20 and MMP-21 were not expressed by any of them. The other MMPs showed variable expression, which was dependent on passage number. Primary cells displayed a similar MMP-expression pattern as the cell-lines. In U251 and U373 cells expression of MMP-9 and MMP-19 was stimulated by TNF-α. MMP-1 mRNA expression was significantly increased in U373 cells, but not in U251 cells by this cytokine. Whereas TGF-β1 had no impact on MMP expression in U251 cells, it significantly induced MMP-11 and MMP-24 expression in U373 cells.</p> <p>Conclusions</p> <p>Literature-data and our own results suggest that the expression pattern of MMPs is highly variable, dependent on the cell-line and the cell-culture conditions used and that also regulation of MMP expression by cytokines is cell-line dependent. This is of high impact for the transfer of cell-culture experiments to clinical implementation.</p

A study of CP violation and measurement of the CKM angle γ in B0→ DK∗0 decays

Two measurements of CP observables in B0 → DK∗0 decays are presented, where D represents a superposition of D0 and D0-bar states. The measurements use samples of proton-proton collision data collected with the LHCb detector at centre-of-mass energies of 7, 8, and 13 TeV. The first measurement uses 5 fb−1 of data with the D meson reconstructed in the two-body final states K+π−, π+K−, K+K-, and π+π−, and, for the first time, in the four-body final states K+π−π+π−, π+K−π+π-, and π+π-π+π−. First observations of the decays B0 → D(π+K−)K∗0 and B0 → D(π+π−π+π−)K∗0 are obtained, and a set of observables comprising yield ratios and asymmetries is studied. The second measurement studies D-meson decays to the three-body final states KS0π+π− and KS0K+K− in a binned Dalitz plot analysis using 9 fb−1 of data. The CP observables from both measurements are interpreted together to determine the CP-violating weak phase γ = (77+8-9)◦. This is the world’s most precise determination using only B0-meson decays and is in agreement with the prediction of the Standard Model. The world’s best measurements of the hadronic parameters r_B = 0.258+0.022-0.023 and δB0 = (200 ± 8)◦ are also presented.</p

Evaluating the Drivers of Quaternary Dust Fluxes to the Western North Pacific: East Asian Dustiness and Northern Hemisphere Gustiness

Quantifying variability in, and identifying the mechanisms behind, East Asian dust production and transport across the last several million years is essential for constraining future dust emissions and deposition. Our current understanding of East Asian dust dynamics through the Quaternary is primarily limited to low-resolution records from the North Pacific Ocean, those from the Chinese Loess Plateau (CLP), and paleoenvironmental reconstructions from arid basins. All are susceptible to sediment winnowing and focusing as well as input of poorly constrained or unidentified non-dust detrital material. To avoid these limitations, we examine high-resolution, constant flux proxy-derived dust fluxes from the North Pacific and find evidence for higher glacial dust fluxes in the late Pliocene-early Pleistocene compared to the late Pleistocene-Holocene. Our results suggest decreasing dust transported to the mid-latitude North Pacific Ocean from eastern Asia across the Quaternary. This observation is ostensibly at odds with previous dust records from marine sediments and the CLP, and with the perception of higher East Asian dust production and transport during the late Pleistocene associated with the amplification of glaciations. We provide three possible scenarios to describe the ∼2,700-ky evolution of eastern Asia glacial dust dynamics, and discuss them in the context of sediment production, availability, and atmospheric circulation. Our data and proposed driving mechanisms not only raise questions about the framework typically used to interpret dust archives from East Asia and the North Pacific Ocean, but also provide a roadmap for hypothesis testing and future work necessary to produce better-constrained records of paleo-dust fluxes

Recognition of prostate-specific antigenic peptide determinants by human CD4 and CD8 T cells

It is now becoming accepted that one is not tolerant to all the determinants of self proteins: the T cell repertoire directed to some sequences in self proteins is intact and can be activated. When a self protein is exclusively expressed by tumour cells, the T cell repertoire directed to the particular self antigen can potentially be activated to attack the tumour: this would amount to induction of a beneficial autoimmune response. Prostate cancer offers a unique opportunity for activation of a tumour-specific immune response owing to the exclusive synthesis of prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSM) by prostatic tissue and prostate tumour cells. In this study we examine the CD4 and CD8 T cell repertoires specific for peptides of PSA and PSM in normal human male individuals, using short-term, peptide antigen-driven CD4 and CD8 T cell lines. We show that short-term, CD4 T cell lines derived from six HLA-DR4 individuals showed strong proliferative responses to six of 10 tested peptides of PSA, selected as to contain a DR4 binding motif. Short-term, CD8 T cell lines from three HLA-A1 individuals showed specific cytolytic activity for autologous targets loaded with five of five tested peptides of PSA and PSM, selected to possess an HLA-A1 binding motif. One of the peptides chosen is termed a ‘dual-motif’ peptide, as it encodes determinants for both CD4 and CD8 T cells. These results, indicating the existence of CD4 and CD8 T cells against determinants of the self proteins, PSA and PSM, in healthy male individuals reveal the potential of the T cell repertoire from the typical prostate cancer patient to eradicate prostate tumours upon being appropriately activated

Search for dark photons produced in 13 TeV pp collisions

Searches are performed for both promptlike and long-lived dark photons, A′, produced in proton-proton collisions at a center-of-mass energy of 13 TeV, using A′→μ+μ- decays and a data sample corresponding to an integrated luminosity of 1.6 fb-1 collected with the LHCb detector. The promptlike A′ search covers the mass range from near the dimuon threshold up to 70 GeV, while the long-lived A′ search is restricted to the low-mass region 214 &lt; m(A′) &lt; 350 MeV. No evidence for a signal is found, and 90% confidence level exclusion limits are placed on the γ-A′ kinetic-mixing strength. The constraints placed on promptlike dark photons are the most stringent to date for the mass range 10.6 &lt; m(A′) &lt; 70 GeV, and are comparable to the best existing limits for m(A′) &lt; 0.5 GeV. The search for long-lived dark photons is the first to achieve sensitivity using a displaced-vertex signature

Observation of D0 meson decays to π+π−μ+μ− and K+K−μ+μ− final states

The first observation of the D0→π+π−μ+μ− and D0→K+K−μ+μ− decays is reported using a sample of proton-proton collisions collected by LHCb at a center-of-mass energy of 8 TeV, and corresponding to 2  fb^−1 of integrated luminosity. The corresponding branching fractions are measured using as normalization the decay D0→K−π+[μ+μ−]ρ0/ω, where the two muons are consistent with coming from the decay of a ρ0 or ω meson. The results are B(D0→π+π−μ+μ−)=(9.64±0.48±0.51±0.97)×10^−7 and B(D0→K+K−μ+μ−)=(1.54±0.27±0.09±0.16)×10^−7, where the uncertainties are statistical, systematic, and due to the limited knowledge of the normalization branching fraction. The dependence of the branching fraction on the dimuon mass is also investigated