Circulating tumor DNA as a marker of treatment response in BRAF V600E mutated non-melanoma solid tumors

Purpose: We evaluated longitudinal tracking of BRAF V600E in circulating cellfree DNA (cfDNA) as a marker of treatment response to BRAF inhibitor (BRAFi) combination therapies in non-melanoma solid tumors included in the Copenhagen Prospective Personalized Oncology (CoPPO) program. Experimental design: Patients with BRAF V600E-mutated tumors were treated with combination therapies including BRAFi. Quantification of mutant cfDNA from plasma was determined and correlated to clinical outcomes. Exome sequencing was performed to identify possible resistance mutations. Results: Twenty-three patients had BRAF-mutated tumors out of 455 patients included in CoPPO and 17 started BRAFi combination (EGFRi/MEKi) therapy. Tumor responses were achieved in 8 out of 16 evaluable patients and the median overalland progression-free survival (OS and PFS) was 15 and 4.8 months, respectively. Longitudinal measurements of BRAF V600E-mutant cfDNA indicated disease progression prior to radiological evaluation and a reduction in the mutant fraction of more than 50% after 4 and 12 weeks of therapy was associated with a significantly longer PFS (p=0.003 and p=0.029) and OS (p=0.029 and p=0.017). Furthermore, the baseline mutant fraction and total level of cfDNA positively correlated with tumor burden (p=0.026 and p=0.024). Finally, analysis of cfDNA at progression revealed novel mutations potentially affecting the MAPK pathway. Conclusion: BRAFi combination therapies showed a response rate of 50% in BRAF V600E-mutated non-melanoma tumors. The fraction of BRAF-mutant cfDNA represent a sensitive indicator for clinical outcomes with plasma collected at week 4 and 12 as crucial time points for monitoring response and disease progression.This study was supported by the Danish Cancer Society, The Harboe Foundation, and the Oncological Research Fund, Department of Oncology, Copenhagen University Hospital, Denmark

Thermostable Branched-Chain Amino Acid Transaminases From the Archaea Geoglobus acetivorans and Archaeoglobus fulgidus: Biochemical and Structural Characterization

This is the final version. Available on open access from Frontiers Media via the DOI in this recordTwo new thermophilic branched chain amino acid transaminases have been identified within the genomes of different hyper-thermophilic archaea, Geoglobus acetivorans, and Archaeoglobus fulgidus. These enzymes belong to the class IV of transaminases as defined by their structural fold. The enzymes have been cloned and over-expressed in Escherichia coli and the recombinant enzymes have been characterized both biochemically and structurally. Both enzymes showed high thermostability with optimal temperature for activity at 80 and 85°C, respectively. They retain good activity after exposure to 50% of the organic solvents, ethanol, methanol, DMSO and acetonitrile. The enzymes show a low activity to (R)-methylbenzylamine but no activity to (S)-methylbenzylamine. Both enzymes have been crystallized and their structures solved in the internal aldimine form, to 1.9 Å resolution for the Geoglobus enzyme and 2.0 Å for the Archaeoglobus enzyme. Also the Geoglobus enzyme structure has been determined in complex with the amino acceptor α-ketoglutarate and the Archaeoglobus enzyme in complex with the inhibitor gabaculine. These two complexes have helped to determine the conformation of the enzymes during enzymatic turnover and have increased understanding of their substrate specificity. A comparison has been made with another (R) selective class IV transaminase from the fungus Nectria haematococca which was previously studied in complex with gabaculine. The subtle structural differences between these enzymes has provided insight regarding their different substrate specificities.Biotechnology & Biological Sciences Research Council (BBSRC

Sequential modulations of the Simon effect depend on episodic retrieval

Sequential modulations of conflict effects, like the reduction of the Simon effect after incompatible trials, have been taken to reflect the operation of a proactive control mechanism commonly called conflict monitoring. However, such modulations are often contaminated by episodic effects like priming and stimulus-response feature integration. It has previously been observed that if the episodic representation of a conflicting trial is altered by rotating the stimulus framing 180° around its axis, the subsequent “conflict adaptation” pattern is eliminated. In Experiment 1, we replicate the findings and provide the basic episodic interpretation. In Experiment 2, we extend the framework to include rotations of 90°, and verify that the episodic effects generalize to scenarios of neutral compatibility. Finally, in Experiment 3, we add complete, 360° rotations, and show that the episodic manipulation by itself does not eliminate the conflict adaptation patterns – as long as conditions favor episodic retrieval. The experiments are argued to demonstrate that an episodic account of the conflict adaptation effect can most parsimoniously account for the behavioral effects without relying on higher order cognition. Accordingly, we conclude that conflict adaptation can be understood either as critically depending on episodic retrieval, or alternatively reflecting only episodic retrieval itself

Real-space mapping of tailored sheet and edge plasmons in graphene nanoresonators

Plasmons in graphene nanoresonators have many potential applications in photonics and optoelectronics, including room-temperature infrared and terahertz photodetectors, sensors, reflect arrays or modulators1, 2, 3, 4, 5, 6, 7. The development of efficient devices will critically depend on precise knowledge and control of the plasmonic modes. Here, we use near-field microscopy8, 9, 10, 11 between λ0 = 10–12 μm to excite and image plasmons in tailored disk and rectangular graphene nanoresonators, and observe a rich variety of coexisting Fabry–Perot modes. Disentangling them by a theoretical analysis allows the identification of sheet and edge plasmons, the latter exhibiting mode volumes as small as 10−8λ03. By measuring the dispersion of the edge plasmons we corroborate their superior confinement compared with sheet plasmons, which among others could be applied for efficient 1D coupling of quantum emitters12. Our understanding of graphene plasmon images is a key to unprecedented in-depth analysis and verification of plasmonic functionalities in future flatland technologies.Peer ReviewedPostprint (author's final draft

Reaction rates and transport in neutron stars

Understanding signals from neutron stars requires knowledge about the transport inside the star. We review the transport properties and the underlying reaction rates of dense hadronic and quark matter in the crust and the core of neutron stars and point out open problems and future directions.Comment: 74 pages; commissioned for the book "Physics and Astrophysics of Neutron Stars", NewCompStar COST Action MP1304; version 3: minor changes, references updated, overview graphic added in the introduction, improvements in Sec IV.A.

An Open-System Quantum Simulator with Trapped Ions

The control of quantum systems is of fundamental scientific interest and promises powerful applications and technologies. Impressive progress has been achieved in isolating the systems from the environment and coherently controlling their dynamics, as demonstrated by the creation and manipulation of entanglement in various physical systems. However, for open quantum systems, engineering the dynamics of many particles by a controlled coupling to an environment remains largely unexplored. Here we report the first realization of a toolbox for simulating an open quantum system with up to five qubits. Using a quantum computing architecture with trapped ions, we combine multi-qubit gates with optical pumping to implement coherent operations and dissipative processes. We illustrate this engineering by the dissipative preparation of entangled states, the simulation of coherent many-body spin interactions and the quantum non-demolition measurement of multi-qubit observables. By adding controlled dissipation to coherent operations, this work offers novel prospects for open-system quantum simulation and computation.Comment: Pre-review submission to Nature. For an updated and final version see publication. Manuscript + Supplementary Informatio

Prognostic impact of CD4-positive T cell subsets in early breast cancer : a study based on the FinHer trial patient population

Background: The clinical importance of tumor-infiltrating cluster of differentiation 4 (CD4) T cells is incompletely understood in early breast cancer. We investigated the clinical significance of CD4, forkhead box P3 (FOXP3), and B cell attracting chemokine leukocyte chemoattractant-ligand (C-X-C motif) 13 (CXCL13) in early breast cancer. Methods: The study is based on the patient population of the randomized FinHer trial, where 1010 patients with early breast cancer were randomly allocated to adjuvant chemotherapy containing either docetaxel or vinorelbine, and human epidermal growth factor receptor 2 (HER2)-positive patients were also allocated to trastuzumab or no trastuzumab. Breast cancer CD4, FOXP3, and CXCL13 contents were evaluated using quantitative real-time polymerase chain reaction (qRT-PCR), and their influence on distant disease-free survival (DDFS) was examined using univariable and multivariable Cox regression and Kaplan-Meier estimates in the entire cohort and in selected molecular subgroups. Interactions between variables were analyzed using Cox regression. The triple-negative breast cancer (TNBC) subset of the HE10/97 randomized trial was used for confirmation. Results: High CXCL13 was associated with favorable DDFS in univariable analysis, and independently in multivariable analysis (HR 0.44, 95% CI 0.29-0.67, P Conclusions: The results provide a high level of evidence that humoral immunity influences the survival outcomes of patients with early breast cancer, in particular of those with TNBC.Peer reviewe

Out-of-equilibrium physics in driven dissipative coupled resonator arrays

Coupled resonator arrays have been shown to exhibit interesting many- body physics including Mott and Fractional Hall states of photons. One of the main differences between these photonic quantum simulators and their cold atoms coun- terparts is in the dissipative nature of their photonic excitations. The natural equi- librium state is where there are no photons left in the cavity. Pumping the system with external drives is therefore necessary to compensate for the losses and realise non-trivial states. The external driving here can easily be tuned to be incoherent, coherent or fully quantum, opening the road for exploration of many body regimes beyond the reach of other approaches. In this chapter, we review some of the physics arising in driven dissipative coupled resonator arrays including photon fermionisa- tion, crystallisation, as well as photonic quantum Hall physics out of equilibrium. We start by briefly describing possible experimental candidates to realise coupled resonator arrays along with the two theoretical models that capture their physics, the Jaynes-Cummings-Hubbard and Bose-Hubbard Hamiltonians. A brief review of the analytical and sophisticated numerical methods required to tackle these systems is included.Comment: Chapter that appeared in "Quantum Simulations with Photons and Polaritons: Merging Quantum Optics with Condensed Matter Physics" edited by D.G.Angelakis, Quantum Science and Technology Series, Springer 201

Combustion in thermonuclear supernova explosions

Type Ia supernovae are associated with thermonuclear explosions of white dwarf stars. Combustion processes convert material in nuclear reactions and release the energy required to explode the stars. At the same time, they produce the radioactive species that power radiation and give rise to the formation of the observables. Therefore, the physical mechanism of the combustion processes, as reviewed here, is the key to understand these astrophysical events. Theory establishes two distinct modes of propagation for combustion fronts: subsonic deflagrations and supersonic detonations. Both are assumed to play an important role in thermonuclear supernovae. The physical nature and theoretical models of deflagrations and detonations are discussed together with numerical implementations. A particular challenge arises due to the wide range of spatial scales involved in these phenomena. Neither the combustion waves nor their interaction with fluid flow and instabilities can be directly resolved in simulations. Substantial modeling effort is required to consistently capture such effects and the corresponding techniques are discussed in detail. They form the basis of modern multidimensional hydrodynamical simulations of thermonuclear supernova explosions. The problem of deflagration-to-detonation transitions in thermonuclear supernova explosions is briefly mentioned.Comment: Author version of chapter for 'Handbook of Supernovae,' edited by A. Alsabti and P. Murdin, Springer. 24 pages, 4 figure