Modeling of Personalized Treatments in Colon Cancer Based on Preclinical Genomic and Drug Sensitivity Data

The current standard therapies for advanced, recurrent or metastatic colon cancer are the 5-fluorouracil and oxaliplatin or irinotecan schedules (FOxFI) +/− targeted drugs cetuximab or bevacizumab. Treatment with the FOxFI cytotoxic chemotherapy regimens causes significant toxicity and might induce secondary cancers. The overall low efficacy of the targeted drugs seen in colon cancer patients still is hindering the substitution of the chemotherapy. The ONCOTRACK project developed a strategy to identify predictive biomarkers based on a systems biology approach, using omics technologies to identify signatures for personalized treatment based on single drug response data. Here, we describe a follow-up project focusing on target-specific drug combinations. Back- ground for this experimental preclinical study was that, by analyzing the tumor growth inhibition in the PDX models by cetuximab treatment, a broad heterogenic response from complete regression to tumor growth stimulation was observed. To provide confirmation of the hypothesis that drug combinations blocking alternatively activated oncogenic pathways may improve therapy outcomes, 25 models out of the well-characterized ONCOTRACK PDX panel were subjected to treatment with a drug combination scheme using four approved, targeted cancer drugs

A schematic model for QCD I: Low energy meson states

A simple model for QCD is presented, which is able to reproduce the meson spectrum at low energy. The model is a Lipkin type model for quarks coupled to gluons. The basic building blocks are pairs of quark-antiquarks coupled to a definite flavor and spin. These pairs are coupled to pairs of gluons with spin zero. The multiplicity problem, which dictates that a given experimental state can be described in various manners, is removed when a particle-mixing interaction is turned on. In this first paper of a series we concentrates on the discussion of meson states at low energy, the so-called zero temperature limit of the theory. The treatment of baryonic states is indicated, also.Comment: 29 pages, 6 figures. submitted to Phys. Rev.

Tackling Exascale Software Challenges in Molecular Dynamics Simulations with GROMACS

GROMACS is a widely used package for biomolecular simulation, and over the last two decades it has evolved from small-scale efficiency to advanced heterogeneous acceleration and multi-level parallelism targeting some of the largest supercomputers in the world. Here, we describe some of the ways we have been able to realize this through the use of parallelization on all levels, combined with a constant focus on absolute performance. Release 4.6 of GROMACS uses SIMD acceleration on a wide range of architectures, GPU offloading acceleration, and both OpenMP and MPI parallelism within and between nodes, respectively. The recent work on acceleration made it necessary to revisit the fundamental algorithms of molecular simulation, including the concept of neighborsearching, and we discuss the present and future challenges we see for exascale simulation - in particular a very fine-grained task parallelism. We also discuss the software management, code peer review and continuous integration testing required for a project of this complexity.Comment: EASC 2014 conference proceedin

A schematic model for QCD at finite temperature

The simplest version of a class of toy models for QCD is presented. It is a Lipkin-type model, for the quark-antiquark sector, and, for the gluon sector, gluon pairs with spin zero are treated as elementary bosons. The model restricts to mesons with spin zero and to few baryonic states. The corresponding energy spectrum is discussed. We show that ground state correlations are essential to describe physical properties of the spectrum at low energies. Phase transitions are described in an effective manner, by using coherent states. The appearance of a Goldstone boson for large values of the interaction strength is discussed, as related to a collective state. The formalism is extended to consider finite temperatures. The partition function is calculated, in an approximate way, showing the convenience of the use of coherent states. The energy density, heat capacity and transitions from the hadronic phase to the quark-gluon plasma are calculated.Comment: 33 pages, 11 figure

Fermion-Boson Interactions and Quantum Algebras

Quantum Algebras (q-algebras) are used to describe interactions between fermions and bosons. Particularly, the concept of a su_q(2) dynamical symmetry is invoked in order to reproduce the ground state properties of systems of fermions and bosons interacting via schematic forces. The structure of the proposed su_q(2) Hamiltonians, and the meaning of the corresponding deformation parameters, are discussed.Comment: 20 pages, 10 figures. Physical Review C (in press

Assessment of patient-derived tumour xenografts (PDXs) as a discovery tool for cancer epigenomics

Background: The use of tumour xenografts is a well-established research tool in cancer genomics but has not yet been comprehensively evaluated for cancer epigenomics. Methods: In this study, we assessed the suitability of patient-derived tumour xenografts (PDXs) for methylome analysis using Infinium 450 K Beadchips and MeDIP-seq. Results: Controlled for confounding host (mouse) sequences, comparison of primary PDXs and matching patient tumours in a rare (osteosarcoma) and common (colon) cancer revealed that an average 2.7% of the assayed CpG sites undergo major (Δβ ≥ 0.51) methylation changes in a cancer-specific manner as a result of the xenografting procedure. No significant subsequent methylation changes were observed after a second round of xenografting between primary and secondary PDXs. Based on computational simulation using publically available methylation data, we additionally show that future studies comparing two groups of PDXs should use 15 or more samples in each group to minimise the impact of xenografting-associated changes in methylation on comparison results. Conclusions: Our results from rare and common cancers indicate that PDXs are a suitable discovery tool for cancer epigenomics and we provide guidance on how to overcome the observed limitations

A weak characterization of slow variables in stochastic dynamical systems

We present a novel characterization of slow variables for continuous Markov processes that provably preserve the slow timescales. These slow variables are known as reaction coordinates in molecular dynamical applications, where they play a key role in system analysis and coarse graining. The defining characteristics of these slow variables is that they parametrize a so-called transition manifold, a low-dimensional manifold in a certain density function space that emerges with progressive equilibration of the system's fast variables. The existence of said manifold was previously predicted for certain classes of metastable and slow-fast systems. However, in the original work, the existence of the manifold hinges on the pointwise convergence of the system's transition density functions towards it. We show in this work that a convergence in average with respect to the system's stationary measure is sufficient to yield reaction coordinates with the same key qualities. This allows one to accurately predict the timescale preservation in systems where the old theory is not applicable or would give overly pessimistic results. Moreover, the new characterization is still constructive, in that it allows for the algorithmic identification of a good slow variable. The improved characterization, the error prediction and the variable construction are demonstrated by a small metastable system

Double conditional human embryonic kidney cell line based on FLP and ΦC31 mediated transgene integration

<p>Abstract</p> <p>Background</p> <p>FLP recombinase mediated integration into a pre-integrated FRT site is routinely used to generate highly reproducible stable transgenic cell lines. In this study, we broaden the system of site specific integration by introducing ΦC31 integrase mediated integration into attP sites.</p> <p>Results</p> <p>We generated a HEK293 host cell line with a single copy FRT as well as an attP site allowing site specific integration of two distinct transgenes. To achieve conditional control, we used the tetracycline and Shld1 inducible systems. By introducing fluorescent reporters we show that integration and induction of two transgenes are completely independent. We applied this new technique to investigate the effect of HNF4α on proliferation of HEK293 cells by introducing HNF4α into each integration site. We obtained in two independent cell lines highly reproducible results that prove the usefulness of this novel HEK-attP/FRT cell line.</p> <p>Conclusions</p> <p>In this study we have established and applied a HEK-attP/FRT cell line that allows site specific integration of two conditional transgenes using the FLP recombinase as well as the ΦC31 integrase.</p

Serum Peptidome Profiling Revealed Platelet Factor 4 as a Potential Discriminating Peptide Associated With Pancreatic Cancer

Purpose: Mass spectrometry-based serum peptidome profiling is a promising tool to identify novel disease-associated biomarkers, but is limited by preanalytical factors and the intricacies of complex data processing. Therefore, we investigated whether standardized sample protocols and new bioinformatic tools combined with external data validation improve the validity of peptidome profiling for the discovery of pancreatic cancer associated serum markers. Experimental Design: For discovery study, two sets of sera from patients with pancreatic cancer (n=40) and healthy controls (n=40) were obtained from two different clinical centers. For external data validation, we collected an independent set of samples from patients (n=20) and healthy controls (n=20). Magnetic beads (MB) with different surface functionalities were used for peptidome fractionation followed by MALDI-TOF MS. Data evaluation was carried out comparing two different bioinformatic strategies. Following proteome database search the matching candidate peptide was verified by MALDI-TOF MS after specific antibody-based immunoaffinity chromatography and independently confirmed by an ELISA assay. Results: Two significant peaks (m/z 3884; 5959) achieved a sensitivity of 86.3% and specificity of 97.6% for the discrimination of patients and healthy controls in the external validation set. Adding peak m/z 3884 to conventional clinical tumor markers (CA 19-9 and CEA) improved sensitivity and specificity as shown by ROC analysis (AUROCcombined=1.00). Mass spectrometry based m/z 3884 peak identification and following immunological quantitation revealed platelet factor 4 as the corresponding peptide. Conclusions: MALDI-TOF MS based serum peptidome profiling allowed the discovery and validation of platelet factor 4 as a new discriminating marker in pancreatic cancer